Circadian Rhythm Disruption Promotes Lung Tumorigenesis
Open accessAbstract
Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression.
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- Findingown data
Per2 mutant cells with high c-Myc showed increased glucose use for the TCA cycle, detected by M4 labeling of TCA cycle intermediates.
“Increased use of glucose for the TCA cycle was detected as determined by carbon 4 labeling (M4) of TCA cycle intermediates (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
In K and KP mice, whole-animal loss of Per2 function increased tumor burden and tumor grade.
“both K (Figure S1A and S1B) and KP (Figure 1G and 1H) animals that had systemic Per2 loss-of-function exhibited increased tumor burden and grade.”
Quote in the paperSubstantial claim - Findingown data
In KP mice, jet lag after tumor initiation decreased survival, with a median survival of 9 days.
“animals placed in jet lag post-tumor initiation (jet lag progression) conditions showed decreased survival (9 days median survival) (p<0.01; Figure 1f)”
Quote in the paperSubstantial claim - Findingown data
In the KrasLA2 model, no increase in tumorigenesis was observed in other sporadic Kras-driven tumors.
“We did not observe increased tumorigenesis in other sporadic Kras-driven tumors in this model (data not shown).”
Quote in the paperSubstantial claim - Findingown data
In KP mice, jet lag beginning before tumor initiation significantly increased the percentage of high-grade grade 3 and 4 tumors compared with LD12:12 controls.
“we did observe a significant increase in the percentage of high-grade tumors in this cohort compared to LD12:12 animals (grade 3 and 4; p<0.05; Figure 1e)”
Quote in the paperSubstantial claim
- Findingown data
Per2 mutant cells showed significantly increased glutamine consumption, indicating greater glutamine usage.
“we observed a significant increase in the levels of glutamine consumption in Per2 mutant cells, indicative of increased glutamine usage (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Conditional Bmal1 loss in KP tumors did not increase tumor burden.
“there was no increase in tumor burden in KP tumors with conditional Bmal1 (Bmal1Δ/Δ) loss (Figure S2A)”
Quote in the paperSubstantial claim - Findingown data
In KP lung tumors, low PER2 expression was associated with enrichment of MYC signatures MYC_UP.V1_UP and DANG_MYC_TARGETS_UP.
“tumors with low levels of PER2 were enriched in MYC signatures (MYC_UP.V1_UP, DANG_MYC_TARGETS_UP)”
Quote in the paperSubstantial claim - Findingown data
Isogenic C57BL/6 KP murine lung cancer cells with CRISPR/Cas9 Per2 knockout using sgPer2.1 and sgPer2.3 showed greater proliferation in low-density culture.
“Cells with CRISPR/Cas9-based knockout of Per2 (sgPer2.1 and sgPer2.3) displayed greater proliferation in low-density culture conditions (Figure 2E, 2F and 2G)”
Quote in the paperSubstantial claim - Findingown data
Tumor-specific deletion of Bmal1 accelerated lung tumor progression in the K model.
“Loss of Bmal1 (Bmal1Δ/Δ) in tumors accelerated lung tumor progression in the K model (Figure 2A, 2B and 2C).”
Quote in the paperSubstantial claim - Findingown data
K and KP Per2m/m mouse embryonic fibroblasts proliferated faster than Per2+/+ controls by population doublings and EdU incorporation.
“K and KP Per2m/m MEFs proliferated faster than the Per2+/+ controls based on population doublings (Figure S3A and S3B) and EdU incorporation (Figure 2I).”
Quote in the paperSubstantial claim - Findingown data
KP; Per2m/m cells produced more colonies in low-density and 3D agar assays.
“KP; Per2m/m cells also produced more colonies in low density (Figure 2J) and 3D agar (Figure 2K) assays”
Quote in the paperSubstantial claim - Findingown data
Per2 CRISPR-knockout KP cells formed tumors after subcutaneous transplantation into congenic immunocompetent C57BL/6 mice.
“and tumor formation following subcutaneous transplantation in congenic immunocompetent C57BL/6 animals (Figure 2H).”
Quote in the paperSubstantial claim - Findingown data
In human lung adenocarcinoma TCGA data, ARNTL, CRY2, and PER3 expression decreased significantly in higher-grade T3 tumors compared with lower-grade T1 tumors.
“we observed that ARNTL, CRY2 and PER3 expression decreased significantly in higher grade (T3) compared to lower grade (T1) tumors (Figure S4A).”
Quote in the paperSubstantial claim - Findingown data
In KP mice, jet lag imposed during tumor progression significantly increased lung tumor burden.
“Animals placed in jet lag during tumor progression for 8-weeks post-infection had a significant increase in the lung tumor burden (p<0.05; Figure 1d)”
Quote in the paperSubstantial claim - Findingown data
In KP mice, jet lag beginning before tumor initiation caused a modest but non-significant increase in tumor burden.
“Jet lag starting a week prior to tumor initiation (jet lag initiation) led to a modest, but non-significant increase in tumor burden (Figure 1d)”
Quote in the paperNot a substantial claim - Findingown data
Kras mutant mouse embryonic fibroblasts lacking Per2 function were more sensitive to transformation after c-Myc or E1A overexpression than Per2+/+ cells.
“Kras mutant MEFs lacking Per2 function showed increased sensitivity to cellular transformation upon overexpression of c-Myc or adenovirus early region 1A (E1A) oncogenes compared to Per2+/+”
Quote in the paperSubstantial claim - Findingown data
KP Per2 mutant cells had higher glucose consumption and lactate excretion than Per2+/+ cells.
“KP Per2 mutant cells had increased rates of glucose consumption and increased levels of lactate excretion compared to Per2+/+ cells (Figure 4A).”
Quote in the paperSubstantial claim - Premisecitation
The jet lag protocol used here has been shown to disrupt core circadian gene oscillations in multiple tissues.
“this protocol has been shown to disrupt the oscillations of the core circadian genes in multiple tissues (Filipski et al., 2005; Lee et al., 2010; Thaiss et al., 2014).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Systemic genetic loss of circadian function enhances lung tumorigenesis in two independent Kras-driven genetically engineered mouse models.
“These data further support the conclusion that systemic circadian rhythm disruption by genetic loss-of-function enhances lung tumorigenesis in two independent Kras-driven GEMMs.”
Quote in the paperSubstantial claim - Interpretationown data
Physiologic circadian disruption produced by changing the light cycle accelerates lung tumorigenesis in mice carrying Kras and p53 mutations.
“Overall, our data demonstrate that physiologic disruption of circadian rhythms by simply altering the light cycle accelerates lung tumorigenesis in the context of Kras and p53 mutations.”
Quote in the paperSubstantial claim - Interpretationown data
Physiologic or genetic Bmal1/Per2 circadian disruption can cooperate with Kras and p53 mutations to promote lung tumorigenesis.
“Our study illustrates that physiologic or genetic (Bmal1/Per2) circadian can cooperate with Kras and p53 to promote lung tumorigenesis.”
Quote in the paperSubstantial claim - Premisecitation
Systemic and tissue-specific disruption of the circadian machinery changes cellular functions such as cell division and metabolism, which are relevant to cancer.
“Systemic and tissue-specific disruption of the circadian machinery leads to changes in cellular functions such as cell division and metabolism, both highly relevant to cancer (Bass and Takahashi, 2010; Hanahan and Weinberg, 2011; Masri et al., 2016; Sahar and Sassone-Corsi, 2009).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Human lung adenocarcinomas with low PER2 may have increased MYC activity.
“suggesting that tumors with low PER2 may have increased MYC activity (Figure S4B).”
Quote in the paperSubstantial claim - Premisecitation
Evidence from cellular and in vivo models indicates that core circadian genes have an important role in carcinogenesis.
“Emerging evidence in several different cellular and in vivo models points to an important role of the core circadian genes in carcinogenesis (Filipski et al., 2005; Fu et al., 2002; Gery et al., 2006; Janich et al., 2011; Kettner et al., 2014; Lee et al., 2010; Puram et al., 2016; Sahar and Sassone-Corsi, 2009; Van Dycke et al., 2015; Wood et al., 2008).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
Increased tumor incidence in circadian mutant animals may result from tumor cell-autonomous loss of circadian regulation that removes a barrier to transformation and tumor progression.
“Our results suggest that increased tumor incidence in circadian mutant animals may be a result of tumor cell-autonomous loss of circadian regulation which eliminates an additional barrier to transformation and tumor progression.”
Quote in the paperSubstantial claim - Interpretationown data
Cell-autonomous circadian control of fundamental cellular processes that are hallmarks of cancer promotes cellular transformation and tumor progression.
“Our results highlight the importance of cell-autonomous circadian control of fundamental cellular processes that are known hallmarks of cancer and promote cellular transformation and tumor progression.”
Quote in the paperSubstantial claim
- May combine two claims. 16
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataK; Per2m/m, K; Bmal1Δ/Δ, and KP; Per2m/m tumors had significantly increased c-Myc protein levels compared with control K and KP tumors.
“K; Per2m/m (p<0.05; Figure 3C and 3F), K; Bmal1Δ/Δ (p<0.01; Figure 3C and 3G) and KP; Per2m/m (p<0.0001; Figure 3D and 3I) tumors showed a significant increase in the protein levels of c-Myc as compared to control samples K and KP tumors”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn human lung adenocarcinoma TCGA data, all core circadian genes except CLOCK had significantly lower transcript levels in matched tumors than in normal lung, while CLOCK was increased.
“With the exception of CLOCK, whose expression was significantly increased in tumors, the transcripts of all the circadian genes were significantly decreased in matched tumors when compared to normal lung (Figure S4A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cancer Genome Atlas Research, 2014
Not checked in the free run.
May combine two claims.
Findingown dataIn KP mice, jet lag during tumor progression shifted tumor grades, reducing grade 2 tumors and increasing grade 3 and 4 tumors.
“a shift in the tumor grades, with fewer grade 2 and more grade 3 and 4 tumors (grade 2 p<0.05; grade 3 p<0.01; Figure 1e)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataK; Per2m/m, K; Bmal1Δ/Δ, and KP; Per2m/m tumors had increased BrdU-positive nuclei compared with controls.
“BrdU incorporation analysis revealed increased BrdU positive nuclei in K; Per2m/m (p<0.001; Figure 4A), K; Bmal1Δ/Δ tumors (p<0.01; Figure 3A) and KP; Per2m/m tumors (p<0.0001; Figure 3B) compared to controls.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataKP Per2m/m cells proliferated faster and had greater clonogenic potential than wild-type KP cells.
“KP Per2m/m cells proliferated faster and had a greater clonogenic potential compared to WT KP cells (Figure S2C and S2D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataKrasLA2/+ mice with germline Per2 mutation or Bmal1 mutation exhibited decreased survival.
“exhibited decreased survival (p<0.05 and p<0.01; Figure 1K)”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningKrasLA2/+; Bmal1−/− mice showed a trend toward more lung tumors and poorer survival than KrasLA2/+; Per2m/m mice.
“KrasLA2/+; Bmal1−/− animals displayed a trend of developing more lung tumors and poorer survival than KrasLA2/+; Per2m/m animals”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataKrasLA2/+ mice with germline Per2 mutation or Bmal1 mutation had increased lung tumor number.
“both KrasLA2/+; Per2m/m and KrasLA2/+; Bmal1−/− animals had an increased lung tumor number (p<0.05 and p<0.01; Figure 1J)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataK; Per2m/m and KP; Per2m/m mice had decreased survival relative to Per2+/+ controls.
“both K; Per2m/m (p<0.01; Figure S1c) and KP; Per2m/m (p<0.001; Figure 1I) animals also had decreased survival compared to wild-type (Per2+/+) controls.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCircadian rhythm disruption can promote lung tumorigenesis, and circadian homeostasis has an important tumor-suppressive role.
“The data presented here demonstrate that circadian rhythm disruption can promote lung tumorigenesis and support an important tumor suppressive role for circadian homeostasis.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataLoss of Per2 or Bmal1 can independently increase c-Myc transcriptional output.
“Therefore loss of Per2 or Bmal1 can independently lead to increased c-Myc transcriptional output.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNight-shift workers have a higher risk of developing cancer and poorer cancer prognosis.
“Epidemiological studies have revealed that individuals who work night-shifts are at higher risk for developing cancer (Hansen, 2001; Kloog et al., 2009; Megdal et al., 2005; Schernhammer et al., 2006; Schernhammer et al., 2001; Viswanathan et al., 2007) or display poorer cancer prognosis (Lis et al., 2003).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationKRAS and P53 are mutated in 30% and 50% of human lung adenocarcinoma patients, respectively, making the GEMMs relevant to a large subset of human lung cancers.
“KRAS and P53 are mutated in 30% and 50% of human lung adenocarcinoma patients respectively, making these GEMMs highly relevant to a large subset of human lung cancers (Cancer Genome Atlas Research, 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cancer Genome Atlas Research, 2014
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLoss of Bmal1 and Clock suppressed leukemogenesis in a prior study, suggesting that circadian disruption can have context-specific effects in different cancers.
“Ebert et al. recently demonstrated that loss of Bmal1 and Clock suppressed leukemogenesis, suggesting that circadian disruption can have context specific effects in different types of cancers (Puram et al., 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Puram et al., 2016 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEarlier reports using germline mutations in circadian components have highlighted a role for circadian rhythm disruption in tumor predisposition.
“Earlier reports using germline mutations in circadian components have highlighted a role for circadian rhythm disruption in tumor predisposition (Filipski et al., 2005; Fu et al., 2002; Gery et al., 2006; Janich et al., 2011; Kettner et al., 2014; Lee et al., 2010; Sahar and Sassone-Corsi, 2009; Van Dycke et al., 2015; Wood et al., 2008).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSystemic loss of Per2 and Bmal1 has different effects on animal circadian behavior.
“Systemic loss of Per2 and Bmal1 has differential effects on circadian behavior of animals (Bunger et al., 2000; Zheng et al., 1999).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataTumor cell-specific deletion of core clock components leads to increased proliferation, c-Myc levels or activation, and metabolic activity.
“We demonstrate through several in vitro and in vivo systems that tumor cell-specific deletion of core clock components leads to increased proliferation, c-Myc levels/activation and metabolic activity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMice assigned to LD12:12 or jet lag conditions were randomized.
“Randomization was used for mice placed into LD12:12 or jet lag.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataLoss of Per2 or Bmal1 accelerated lung cancer despite their differential effects on whole-animal circadian behavior.
“Despite these differences on whole-animal behavior, loss of Per2 or Bmal1 accelerated lung cancer.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The mechanism linking circadian rhythm disruption to cancer development and the way oncogenic events cooperate with clock disruption during initiation and progression are not known.
“Despite several lines of evidence implicating circadian rhythm disruption in cancer, the underlying mechanism that contributes to disease development remains elusive. It is unclear how oncogenic events may cooperate with circadian clock disruption during cancer initiation and progression.”
The paper relies on this without support.
Research on physiologic risk factors such as circadian rhythm disruption has been limited by a lack of rigorous in vivo experimental systems.
“The study of physiologic risk factors, such as circadian rhythm disruption, has been largely hindered by the lack of rigorous in vivo experimental systems.”
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Animal models with environmentally disturbed circadian systems (simulated shift work) indicate that circadian disruption increases cancer progression, possibly through cell cycle dysregulation, DNA damage accumulation, and reduced tumor suppression.
“Findings in animal models with environmentally disturbed circadian systems (simulated shift work) indicate that circadian disruption increases the progression of cancer, possibly through dysregulation of the cell cycle, accumulation of DNA damage, and reduced tumor suppression [49,50,51,52].”
From Shift Work: Disrupted Circadian Rhythms and Sleep—Implications for Health and Well-being (2017) · cites this paper as [51]
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Jet-lag initiation duration differs by one week
MinorThe results say initiation-group mice began jet lag one week before tumor initiation and continued until 13 weeks afterward, a total of 14 weeks. The methods instead say they remained under those conditions for 13 weeks.
“Animals were placed in jet lag either a week prior to tumor-initiation (jet lag initiation) or 5 weeks after lung tumor initiation (jet lag progression) and remained under jet lag conditions until the end of the study 13 weeks post tumor initiation (Figure 1c).”
“Jet lag at ‘Initiation’ was performed by placing animals in altered light conditions a week before tumor initiation and kept under those conditions for 13 weeks.”
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InfluentialAnalysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasPreprint
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InfluentialTranskingdom Control of Microbiota Diurnal Oscillations Promotes Metabolic Homeostasis
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InfluentialCircadian Clock NAD + Cycle Drives Mitochondrial Oxidative Metabolism in Mice
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Night work and breast cancer risk: A systematic review and meta-analysis
Megdal, S. P., Kroenke, C. H., Laden, F., Pukkala, E., & Schernhammer, E. S. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2005.05.010 · Cited by 482 · cited 2× · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Hansen, 2001; Kloog et al., 2009; Megdal et al., 2005; Schernhammer et al., 2006; Schernhammer et al., 2001; Viswanathan et al., 2007) or display poorer cancer prognosis (Lis et al., 2003).”
Storch, K.-F., Paz, C., Signorovitch, J., Raviola, E., Pawlyk, B., Li, T., & Weitz, C. J. (2007) · Cell · doi:10.1016/j.cell.2007.06.045 · Cited by 460 · cited 4× · see citing works
“We utilized several existing circadian mutant alleles which are available from Jackson Laboratories for germline mutant Per2 (Per2tm1Brd/J) (Zheng et al., 1999), germline mutant (Arntltm1Bra/J) (Bunger et al., 2000) and conditional (Arntltm1Weit/J) (Storch et al., 2007) Bmal1.”
InfluentialDeregulated expression of the PER1 , PER2 and PER3 genes in breast cancers
Chen, S., Choo, K., Hou, M., Yeh, K., Kuo, S., & Chang, J. (2005) · Carcinogenesis · doi:10.1093/carcin/bgi075 · Cited by 419 · cited 2× · see citing works
“Cell-autonomous loss of circadian rhythms in human malignancies may occur through both genetic and epigenetic mechanisms (Alhopuro et al., 2010; Chen et al., 2005; Kettner et al., 2014; Taniguchi et al., 2009).”
Modeling of a Human Circadian Mutation Yields Insights into Clock Regulation by PER2
Xu, Y., Toh, K. L., Jones, C. R., Shin, J., Fu, Y., & Ptáček, L. J. (2007) · Cell · doi:10.1016/j.cell.2006.11.043 · Cited by 405 · cited 2× · see citing works
“Interestingly, Kras; Bmal1 / animals displayed a trend of developing more lung tumors and poorer survival than Kras; Per2 animals, which may be explained by Bmal1 loss having a greater impact on circadian rhythm disruption (Bunger et al., 2000; Xu et al., 2007; Zheng et al., 1999).”
Applications of the CRISPR-Cas9 system in cancer biology
Sánchez-Rivera, F. J., & Jacks, T. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3950 · Cited by 405 · cited 2× · see citing works
“3) or a control non-targeting sgRNA (ctrl) (Figure 2D), according to standard procedures (Ran et al., 2013; Sánchez-Rivera and Jacks, 2015; Sayin and Papagiannakopoulos, 2016).”
Self-citationNight Shift Work and the Risk of Endometrial Cancer
Viswanathan, A. N., Hankinson, S. E., & Schernhammer, E. S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2485 · Cited by 338 · cited 2× · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Hansen, 2001; Kloog et al., 2009; Megdal et al., 2005; Schernhammer et al., 2006; Schernhammer et al., 2001; Viswanathan et al., 2007) or display poorer cancer prognosis (Lis et al., 2003).”
The circadian molecular clock creates epidermal stem cell heterogeneity
Janich, P., Pascual, G., Merlos-Suárez, A., Batlle, E., Ripperger, J., Albrecht, U., Cheng, H.-Y. M., Obrietan, K., Di Croce, L., & Benitah, S. A. (2011) · Nature · doi:10.1038/nature10649 · Cited by 326 · cited 4× · see citing works
“…in vivo models points to an important role of the core circadian genes in carcinogenesis (Filipski et al., 2005; Fu et al., 2002; Gery et al., 2006; Janich et al., 2011; Kettner et al., 2014; Lee et al., 2010; Puram et al., 2016; Sahar and Sassone-Corsi, 2009; Van Dycke et al., 2015; Wood et al.,…”
InfluentialPekovic‐Vaughan, V., Gibbs, J. E., Yoshitane, H., Yang, N., Pathiranage, D. R., Guo, B., Sagami, A., Taguchi, K., Bechtold, D. A., Loudon, A. S. I., et al. (2014) · Genes & Development · doi:10.1101/gad.237081.113 · Cited by 325 · cited 2× · see citing works
“Metabolic reprograming of circadian mutant lung cancer cells Circadian rhythms are known to control a number of metabolic processes, including oxidative phosphorylation (Peek et al., 2013), redox homeostasis (Pekovic-Vaughan et al., 2014) and lipid metabolism (Grimaldi et al., 2010).”
Inhibition of Myc family proteins eradicates KRas-driven lung cancer in micePreprint
Soucek, L., Whitfield, J. R., Sodir, N. M., Massó-Vallés, D., Serrano, E., Karnezis, A. N., Swigart, L. B., & Evan, G. I. (2013) · Genes & Development · doi:10.1101/gad.205542.112 · Cited by 299 · cited 2× · see citing works
“C-Myc function has been shown to be essential for lung tumor growth (Soucek et al., 2013) and previously has been implicated in circadian”
Zheng (1999) · doi:10.1038/22659 · Cited by 293 · see citing works
Disrupting Circadian Homeostasis of Sympathetic Signaling Promotes Tumor Development in Mice
Lee, S., Donehower, L. A., Herron, A. J., Moore, D. D., & Fu, L. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010995 · Cited by 286 · cited 11× · see citing works
“C-Myc function has been shown to be essential for lung tumor growth (Soucek et al., 2013) and has been previously implicated in circadian rhythm regulation (Altman et al., 2015; Fu et al., 2002; Lee et al., 2010).”
InfluentialCore circadian clock genes regulate leukemia stem cells in AML
Puram, R. V., Kowalczyk, M. S., de Boer, C. G., Schneider, R. K., Miller, P. G., McConkey, M., Tothova, Z., Tejero, H., Heckl, D., Järås, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.03.015 · Cited by 274 · cited 3× · see citing works
“Ebert et al. recently demonstrated that loss of Bmal1 and Clock suppressed leukemogenesis, suggesting that circadian disruption can have context specific effects in different types of cancers (Puram et al., 2016).”
MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells
Altman, B. J., Hsieh, A. L., Sengupta, A., Krishnanaiah, S. Y., Stine, Z. E., Walton, Z. E., Gouw, A. M., Venkataraman, A., Li, B., Goraksha-Hicks, P., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.003 · Cited by 273 · cited 4× · see citing works
“Recent work has demonstrated that c-Myc dampens circadian oscillations by opposing BMAL1 transcriptional oscillations and disrupting homeostatic glucose and glutamine oscillations (Altman et al., 2015).”
InfluentialLung adenocarcinoma distally rewires hepatic circadian homeostasis
Masri, S., Papagiannakopoulos, T., Kinouchi, K., Liu, Y., Cervantes, M., Baldi, P., Jacks, T., & Sassone-Corsi, P. (2016) · Cell · doi:10.1016/j.cell.2016.04.039 · Cited by 234 · cited 2× · see citing works
“Systemic and tissue-specific disruption of the circadian machinery leads to changes in cellular functions such as cell division and metabolism, both highly relevant to cancer (Bass and Takahashi, 2010; Hanahan and Weinberg, 2011; Masri et al., 2016; Sahar and SassoneCorsi, 2009).”
Self-citationGlobal co-distribution of light at night (LAN) and cancers of prostate, colon, and lung in men
Kloog, I., Haim, A., Stevens, R. G., & Portnov, B. A. (2009) · Chronobiology International · doi:10.1080/07420520802694020 · Cited by 215 · cited 4× · see citing works
“Circadian rhythm disruption through shift work has been linked to increased cancer risk in multiple types of cancer (Hansen, 2001; Kloog et al., 2009; Schernhammer et al., 2001, 2006).”
InfluentialEffects of light and food schedules on liver and tumor molecular clocks in mice
Filipski, E., Innominato, P. F., Wu, M., Li, X.-M., Iacobelli, S., Xian, L.-J., & Levi, F. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji083 · Cited by 200 · cited 7× · see citing works
“Earlier reports using germline mutations in circadian components have highlighted a role for circadian rhythm disruption in tumor predisposition (Filipski et al., 2005; Fu et al., 2002; Gery et al., 2006; Janich et al., 2011; Kettner et al., 2014; Lee et al., 2010; Sahar and Sassone-Corsi, 2009;…”
InfluentialEpigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies
Taniguchi, H., Fernández, A. F., Setién, F., Ropero, S., Ballestar, E., Villanueva, A., Yamamoto, H., Imai, K., Shinomura, Y., & Esteller, M. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0551 · Cited by 182 · cited 2× · see citing works
“Cell-autonomous loss of circadian rhythms in human malignancies may occur through both genetic and epigenetic mechanisms (Alhopuro et al., 2010; Chen et al., 2005; Kettner et al., 2014; Taniguchi et al., 2009).”
Period 2 Mutation Accelerates ApcMin/+ Tumorigenesis
Wood, P. A., Yang, X., Taber, A., Oh, E.-Y., Ansell, C. M., Ayers, S. E., Al-Assaad, Z., Carnevale, K. A., Berger, F. G., Peña, M. M. O., et al. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0196 · Cited by 181 · cited 3× · see citing works
“Emerging evidence in several different cellular and in vivo models points to an important role of the core circadian genes in carcinogenesis (Filipski et al., 2005; Fu et al., 2002; Gery et al., 2006; Janich et al., 2011; Kettner et al., 2014; Lee et al., 2010; Puram et al., 2016; Sahar and Sassone-Corsi, 2009; Van Dy…”
Chronically Alternating Light Cycles Increase Breast Cancer Risk in Mice
Van Dycke, K. C. G., Rodenburg, W., van Oostrom, C. T. M., van Kerkhof, L. W. M., Pennings, J. L. A., Roenneberg, T., van Steeg, H., & van der Horst, G. T. J. (2015) · Current Biology · doi:10.1016/j.cub.2015.06.012 · Cited by 170 · cited 6× · see citing works
“[PubMed: 25417104] Van Dycke KC, Rodenburg W, van Oostrom CT, van Kerkhof LW, Pennings JL, Roenneberg T, van Steeg H, van der Horst GT. Chronically Alternating Light Cycles Increase Breast Cancer Risk in Mice.”
InfluentialCircadian gene variants in cancer
Kettner, N. M., Katchy, C. A., & Fu, L. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.914808 · Cited by 147 · cited 6× · see citing works
“…models points to an important role of the core circadian genes in carcinogenesis (Filipski et al., 2005; Fu et al., 2002; Gery et al., 2006; Janich et al., 2011; Kettner et al., 2014; Lee et al., 2010; Puram et al., 2016; Sahar and Sassone-Corsi, 2009; Van Dycke et al., 2015; Wood et al., 2008).”
InfluentialMullenders, J., Fabius, A. W. M., Madiredjo, M., Bernards, R., & Beijersbergen, R. L. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004798 · Cited by 142 · cited 2× · see citing works
“Interestingly however, there was no increase in tumor burden in KP tumors with conditional Bmal1 (Bmal1Δ/Δ) loss (Figure S2A), suggesting a possible p53-dependent role for Bmal1 as has been suggested by a prior study (Mullenders et al., 2009).”
Mutations in the Circadian Gene CLOCK in Colorectal Cancer
Alhopuro, P., Björklund, M., Sammalkorpi, H., Turunen, M. M., Tuupanen, S., Biström, M., Niittymäki, I., Lehtonen, H. J., Kivioja, T., Launonen, V., et al. (2010) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0086 · Cited by 80 · cited 2× · see citing works
“Cell-autonomous loss of circadian rhythms in human malignancies may occur through both genetic and epigenetic mechanisms (Alhopuro et al., 2010; Chen et al., 2005; Kettner et al., 2014; Taniguchi et al., 2009).”
Circadian timing in cancer treatment: the biological foundation for an integrative approach
Lis, C. G., Grutsch, J. F., Wood, P., You, M., Rich, I., & Hrushesky, W. J. M. (2003) · Integrative Cancer Therapies · doi:10.1177/1534735403002002002 · Cited by 48 · cited 2× · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Hansen, 2001; Kloog et al., 2009; Megdal et al., 2005; Schernhammer et al., 2006; Schernhammer et al., 2001; Viswanathan et al., 2007) or display poorer cancer prognosis (Lis et al., 2003).”
Application of CRISPR-mediated genome engineering in cancer research
Sayin, V. I., & Papagiannakopoulos, T. Y. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.03.029 · Cited by 19 · cited 2× · see citing works
“3) or a control non-targeting sgRNA (ctrl) (Figure 2D), according to standard procedures (Ran et al., 2013; Sánchez-Rivera and Jacks, 2015; Sayin and Papagiannakopoulos, 2016).”
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Transcriptional architecture of the mammalian circadian clock
Takahashi, J. S. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.150 · Cited by 2,637 · see citing works
Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis
Romero, R., Sayin, V. I., Davidson, S. M., Bauer, M. R., Singh, S. X., LeBoeuf, S. E., Karakousi, T. R., Ellis, D. C., Bhutkar, A., Sánchez-Rivera, F. J., et al. (2017) · Nature Medicine · doi:10.1038/nm.4407 · Cited by 652 · see citing works
Self-citationThe aging clock: circadian rhythms and later life
Hood, S., & Amir, S. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90328 · Cited by 621 · see citing works
“These declines in peripheral clocks may have important implications for the susceptibility of aged animals to various disease states, given evidence demonstrating links between loss of rhythmic clock gene expression and the development of metabolic disease states and cancers (94, 95).”
Circadian time signatures of fitness and disease
Bass, J. T., & Lazar, M. A. (2016) · Science · doi:10.1126/science.aah4965 · Cited by 616 · see citing works
Genomics of circadian rhythms in health and disease
Rijo‐Ferreira, F., & Takahashi, J. S. (2019) · Genome Medicine · doi:10.1186/s13073-019-0704-0 · Cited by 537 · see citing works
Embracing cancer complexity: Hallmarks of systemic disease
Swanton, C., Bernard, E., Abbosh, C., André, F., Auwerx, J. H., Balmain, A., Bar‐Sagi, D., Bernards, R., Bullman, S., DeGregori, J. V., et al. (2024) · Cell · doi:10.1016/j.cell.2024.02.009 · Cited by 555 · see citing works
Shift Work: Disrupted Circadian Rhythms and Sleep—Implications for Health and Well-being
James, S. M., Honn, K. A., Gaddameedhi, S., & Van Dongen, H. P. A. (2017) · Current Sleep Medicine Reports · doi:10.1007/s40675-017-0071-6 · Cited by 517 · see citing works
Circadian Mechanisms in Medicine
Allada, R., & Bass, J. (2021) · New England Journal of Medicine · doi:10.1056/nejmra1802337 · Cited by 519 · see citing works
Interplay between Circadian Clock and Cancer: New Frontiers for Cancer Treatment
Sulli, G., Lam, M. T. Y., & Panda, S. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.07.002 · Cited by 484 · see citing works
Circadian rhythm as a therapeutic target
Ruan, W., Yuan, X., & Eltzschig, H. K. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-00109-w · Cited by 501 · see citing works
The emerging link between cancer, metabolism, and circadian rhythms
Masri, S., & Sassone‐Corsi, P. (2018) · Nature Medicine · doi:10.1038/s41591-018-0271-8 · Cited by 406 · see citing works
Circadian rhythms and the gut microbiota: from the metabolic syndrome to cancer
Bishehsari, F., Voigt, R. M., & Keshavarzian, A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-00427-4 · Cited by 378 · see citing works
REV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis
Wang, S., Lin, Y., Yuan, X., Li, F., Guo, L., & Wu, B. (2018) · Nature Communications · doi:10.1038/s41467-018-06568-5 · Cited by 355 · see citing works
The Genomic Landscape and Pharmacogenomic Interactions of Clock Genes in Cancer Chronotherapy
Ye, Y., Xiang, Y., Ozguc, F. M., Kim, Y.-J., Liu, C., Park, P. K., Hu, Q., Diao, L., Lou, Y., Lin, C., et al. (2018) · Cell Systems · doi:10.1016/j.cels.2018.01.013 · Cited by 307 · see citing works
The metastatic spread of breast cancer accelerates during sleep
Diamantopoulou, Z., Castro-Giner, F., Schwab, F. D., Foerster, C., Saini, M., Budinjas, S., Strittmatter, K., Krol, I., Seifert, B., Heinzelmann-Schwarz, V. A., et al. (2022) · Nature · doi:10.1038/s41586-022-04875-y · Cited by 323 · see citing works
Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy
Fendt, S., Frezza, C., & Erez, A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0844 · Cited by 320 · see citing works
Neutrophils instruct homeostatic and pathological states in naive tissues
Casanova-Acebes, M., Nicolás-Ávila, J. A., Li, J. L., García-Silva, S., Balachander, A., Rubio-Ponce, A., Weiss, L., Adrover, J. M., Burrows, K., A-González, N., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20181468 · Cited by 285 · see citing works
Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock
Dong, Z., Zhang, G., Qu, M., Gimple, R. C., Wu, Q., Qiu, Z., Prager, B. C., Wang, X., Kim, L. J. Y., Morton, A. R., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0215 · Cited by 284 · see citing works
“Our findings in fully transformed cancer cells stand in contrast to previous reports that a circadian rhythm and core clock genes function as tumor suppressors during initial tumorigenesis (20,21), suggesting that the role of core clock function in tumor progression may differ based on tumor development stage, cell ty…”
ResultSulli, G., Manoogian, E. N. C., Taub, P. R., & Panda, S. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.07.003 · Cited by 285 · see citing works
Clocks, cancer, and chronochemotherapy
Sancar, A., & Gelder, R. N. V. (2020) · Science · doi:10.1126/science.abb0738 · Cited by 276 · see citing works
“In an innovative model used to study the circadian clock disruption–cancer connection, K-ras and p53were deleted locally in the lung, and mice were subjected to chronic jet lag or Per2 or Bmal1 mutations (77).”
MethodMitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management
Jin, P., Jiang, J., Zhou, L., Huang, Z., Nice, E. C., Huang, C., & Fu, L. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01313-4 · Cited by 282 · see citing works
Interconnection between circadian clocks and thyroid function
Ikegami, K., Refetoff, S., Van Cauter, E., & Yoshimura, T. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0237-z · Cited by 251 · see citing works
KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer
Alam, H., Tang, M., Maitituoheti, M., Dhar, S. S., Kumar, M., Han, C. Y., Ambati, C. R., Amin, S. B., Gu, B., Chen, T.-Y., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.03.005 · Cited by 243 · see citing works
“Of these five genes, the circadian rhythm repressor gene Per2 was particularly interesting for the following reasons: (1) Per2 loss in mouse lung promoted lung tumorigenesis (Papagiannakopoulos et al., 2016); (2) Per2 loss increased glucose metabolism, implicating PER2 in regulation of glycolysis (Papagiannakopoulos e…”
BackgroundHadadi, É., Taylor, W. R., Li, X., Aslan, Y., Vilotte, M., Rivière, J., Duvallet, G., Auriau, C., Dulong, S., Raymond‐Letron, I., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16890-6 · Cited by 223 · see citing works
Dendritic cells direct circadian anti-tumour immune responses
Wang, C., Barnoud, C., Cenerenti, M., Sun, M., Caffa, I., Kizil, B., Bill, R., Liu, Y., Pick, R., Garnier, L., et al. (2022) · Nature · doi:10.1038/s41586-022-05605-0 · Cited by 240 · see citing works
Xie, M., Tang, Q., Nie, J., Zhang, C., Zhou, X., Yu, S., Sun, J., Cheng, X. C., Dong, N., Hu, Y., et al. (2020) · Circulation Research · doi:10.1161/circresaha.119.315502 · Cited by 223 · see citing works
Mollaoglu, G., Jones, A. D., Wait, S. J., Mukhopadhyay, A., Jeong, S., Arya, R. S., Camolotto, S. A., Mosbruger, T. L., Stubben, C., Conley, C. J., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.09.020 · Cited by 208 · see citing works
“Given the complexity of the dataset in terms of a mixture of species, tissue-types, and genotypes, a high-resolution signature discovery approach (Independent Component Analysis, ICA) was employed to characterize global gene expression profiles as described previously (Papagiannakopoulos et al., 2016).”
Self-citationClock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism
Krishnaiah, S., Wu, G., Altman, B. J., Growe, J., Rhoades, S. D., Coldren, F., Venkataraman, A., Olarerin-George, A. O., Francey, L. J., Mukherjee, S., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.019 · Cited by 207 · see citing works
Roles of circadian clocks in cancer pathogenesis and treatment
Lee, Y. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00681-0 · Cited by 201 · see citing works
CRY2 and FBXL3 Cooperatively Degrade c-MYC
Huber, A., Papp, S. J., Chan, A. B., Henriksson, E., Jordan, S. D., Kriebs, A., Nguyen, M., Wallace, M., Li, Z., Metallo, C. M., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.10.012 · Cited by 197 · see citing works
“, 2009) or subjected to experimental jet lag (Papagiannakopoulos et al., 2016; Van Dycke et al., 2015) exhibit altered rates of tumor formation.”
InfluentialSkene, D. J., Skornyakov, E., Chowdhury, N. R., Gajula, R. P., Middleton, B., Satterfield, B. C., Porter, K. I., Van Dongen, H. P. A., & Gaddameedhi, S. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1801183115 · Cited by 176 · see citing works
CRISPR–Cas: a tool for cancer research and therapeutics
Yin, H., Xue, W., & Anderson, D. G. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0166-8 · Cited by 178 · see citing works
Molecular Cogs: Interplay between Circadian Clock and Cell Cycle
Gaucher, J., Montellier, E., & Sassone‐Corsi, P. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.01.006 · Cited by 169 · see citing works
Bmal1 integrates mitochondrial metabolism and macrophage activation
Alexander, R., Liou, Y.-H., Knudsen, N. H., Starost, K. A., Xu, C., Hyde, A. L., Liu, S., Jacobi, D., Liao, N., & Lee, C. (2020) · eLife · doi:10.7554/elife.54090 · Cited by 167 · see citing works
“The circadian rhythm has been implicated in many biological and pathological processes, including the immune response and tumor progression (Hardin and Panda, 2013; Nguyen et al., 2013; Papagiannakopoulos et al., 2016).”
BackgroundCircadian Clock, Cell Division, and Cancer: From Molecules to Organism
Shostak, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040873 · Cited by 167 · see citing works
“Either subjected to chronic jetlag or bearing mutated alleles of Per2 or Bmal1, these animals showed increased tumorigenesis and lower survival rates, which correlated with higher proliferation rates and MYC expression levels in their tumors [103].”
BackgroundZeng, Y., Guo, Z., Wu, M., Chen, F., & Chen, L. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01960-1 · Cited by 184 · see citing works
“Rodent studies con fi rm this view, showing that changes in circadian rhythms can disrupt cell cycles, alter metabolism, promote tumor development, induce tumor cell growth, and trigger tumor-related immune cell remodeling under simulated shift work and chronic jet lag conditions [157 – 160].”
Circadian Rhythms, Disease and Chronotherapy
Lee, Y., Field, J. M., & Sehgal, A. (2021) · Journal of Biological Rhythms · doi:10.1177/07487304211044301 · Cited by 166 · see citing works
“, Bmal1, Per1/2, Cry1/2, Rev-erbα/β) or experimental jet lag (chronic phase shift by altered light schedules) increase the risk of sleep, mood, cardio-metabolic, immune, endocrine, digestive, reproductive, premature aging, neurodegenerative and neoplastic disorders (Kondratov et al., 2006; Alvarez et al., 2008; Musiek…”
BackgroundMolecular Mechanisms of Cancer-Induced Sleep Disruption
Walker, W. H., II, & Borniger, J. C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112780 · Cited by 146 · see citing works
“Building on these findings, Papagiannakopoulos and colleagues examined the influence of genetic and environmental circadian disruption on tumor development in a model of lung cancer [255].”
BackgroundDevelopment and Therapeutic Potential of Small-Molecule Modulators of Circadian Systems
Chen, Z., Yoo, S. H., & Takahashi, J. S. (2017) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010617-052645 · Cited by 153 · see citing works
Circadian rhythms and cancers: the intrinsic links and therapeutic potentials
Zhou, L., Zhang, Z., Nice, E. C., Huang, C., Zhang, W., & Tang, Y. C. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01238-y · Cited by 156 · see citing works
“In addition, disruption of Per2 also accelerated KrasG12D and KrasG12D/p53−/− mutation-mediated lung cancer progression [23].”
BackgroundExploiting Metabolic Vulnerabilities of Cancer with Precision and Accuracy
Wolpaw, A. J., & Dang, C. V. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.11.006 · Cited by 147 · see citing works
“Emerging evidence has shown oncogenic disruption of the clock in cancer cells [83-85].”
BackgroundCancer and stress: NextGen strategies
Cui, B., Peng, F., Lu, J., He, B., Su, Q., Luo, H., Deng, Z., Jiang, T., Su, K., Huang, Y., et al. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.11.005 · Cited by 152 · see citing works
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The Circadian Protein Period2 Suppresses mTORC1 Activity via Recruiting Tsc1 to mTORC1 Complex
Wu, R., Dang, F., Li, P., Wang, P., Xu, Q., Liu, Z., Li, Y., Wu, Y., Chen, Y., & Liu, Y. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.11.006 · Cited by 136 · see citing works
Lee, Y., Lahens, N., Zhang, S. L., Bedont, J., Field, J., & Sehgal, A. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000228 · Cited by 104 · see citing works
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“Loss of these central circadian genes led to elevated c‐MYC expression, inducing metabolic dysregulation.(12) Nevertheless, to our knowledge, CRD‐based tumor behaviors have been studied mainly by using data from the bulk samples derived from genetically engineered in vivo or in vitro models.”
BackgroundEntrainment of the mouse circadian clock: Effects of stress, exercise, and nutrition
Tahara, Y., & Shibata, S. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.12.026 · Cited by 116 · see citing works
Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade
Fortin, B. M., Pfeiffer, S. M., Insua‐Rodríguez, J., Alshetaiwi, H. S., Moshensky, A., Song, W. A., Mahieu, A. L., Chun, S. K., Lewis, A. N., Hsu, A., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01859-0 · Cited by 139 · see citing works
Metabolic rivalry: circadian homeostasis and tumorigenesis
Kinouchi, K., & Sassone‐Corsi, P. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0291-9 · Cited by 125 · see citing works
Animal Cryptochromes: Divergent Roles in Light Perception, Circadian Timekeeping and Beyond
Michael, A. K., Fribourgh, J. L., Gelder, R. N. V., & Partch, C. L. (2016) · Photochemistry and Photobiology · doi:10.1111/php.12677 · Cited by 115 · see citing works
“founded by genetic deletion of various clock components and the subsequent array of cancer phenotypes (131,132).”
BackgroundEvidence for widespread dysregulation of circadian clock progression in human cancer
Shilts, J., Chen, G., & Hughey, J. (2018) · PeerJ · doi:10.7717/peerj.4327 · Cited by 99 · see citing works
“Furthermore, both environmental and genetic disruption of the circadian system promote tumor growth and decrease survival in amousemodel of human lung adenocarcinoma (Papagiannakopoulos et al., 2016).”
The neural addiction of cancer
Magnon, C., & Hondermarck, H. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00556-8 · Cited by 126 · see citing works
Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma
Fekry, B., Ribas‐Latre, A., Baumgartner, C., Deans, J., Kwok, C., Patel, P., Fu, L., Berdeaux, R., Sun, K., Kolonin, M. G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06648-6 · Cited by 107 · see citing works
The phosphorylation switch that regulates ticking of the circadian clock
Narasimamurthy, R., & Virshup, D. M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.006 · Cited by 105 · see citing works
Circadian rhythm and disease: Relationship, new insights, and future perspectives
Neves, A. R., Albuquerque, T., Quintela, T., & Costa, D. R. B. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30815 · Cited by 120 · see citing works
“They found that the transcripts of Per2 and Bmal1 genes significantly decreased which ended in c‐Myc increased expression, enhanced proliferation, and metabolic dysregulation (Papagiannakopoulos et al., 2016).”
BackgroundDisruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer
Chun, S. K., Fortin, B. M., Fellows, R. C., Habowski, A. N., Verlande, A., Song, W. A., Mahieu, A. L., Lefebvre, A. E. Y. T., Sterrenberg, J. N., Vélez, L. M., et al. (2022) · Science Advances · doi:10.1126/sciadv.abo2389 · Cited by 106 · see citing works
Khan, S., Duan, P., Yao, L., & Hou, H. (2018) · International Journal of Genomics · doi:10.1155/2018/8576890 · Cited by 110 · see citing works
“Per2 and BMAL1 lose the ability of inhibiting tumor progression and hence promotes lung cancer [115].”
BackgroundCircadian Clocks and Cancer: Timekeeping Governs Cellular Metabolism
Verlande, A., & Masri, S. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.05.001 · Cited by 102 · see citing works
“PTEN and p53 tumor suppressors also regulate the clock, including downstream signaling cascades involving PI3K/AKT [7, 56, 75].”
BackgroundInfluentialKoritala, B. S. C., Porter, K. I., Arshad, O. A., Gajula, R. P., Mitchell, H. D., Arman, T., Manjanatha, M. G., Teeguarden, J., Dongen, H. P. A. V., McDermott, J., et al. (2021) · Journal of Pineal Research · doi:10.1111/jpi.12726 · Cited by 106 · see citing works
Stokes, K., Nunes, M., Trombley, C., Flôres, D. E. F. L., Wu, G., Taleb, Z., Alkhateeb, A., Banskota, S., Harris, C. R., Love, O. P., et al. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.08.001 · Cited by 94 · see citing works
Microbiome diurnal rhythmicity and its impact on host physiology and disease risk
Nobs, S. P., Tuganbaev, T., & Elinav, E. (2019) · EMBO Reports · doi:10.15252/embr.201847129 · Cited by 90 · see citing works
“For both colorectal [174] and lung cancers [175], jet-lag was found to promote carcinogenesis in mice and humans and it is likely that disruption of microbial rhythmicity in addition to the host clock will influence disease development (Fig 2).”
Cancer in the Fourth Dimension: What Is the Impact of Circadian Disruption?
Pariollaud, M., & Lamia, K. A. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0413 · Cited by 86 · see citing works
“Papagiannakopoulos and colleagues reported an increased lung tumor number and decreased survival upon loss of Bmal1 in an autochthonous KRAS-driven GEMM (KrasLA2/+) that gives rise spontaneously to sporadic tumors in various tissues (47).”
BackgroundClocking cancer: the circadian clock as a target in cancer therapy
Battaglin, F., Chan, P., Pan, Y., Soni, S., Qu, M., Spiller, E. R., Castanon, S. L., Torres, E. T. R., Mumenthaler, S. M., Kay, S. A., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01778-6 · Cited by 88 · see citing works
“p53 or Ras, alteration or knock-out of core clock genes such as Bmal1 and Per can accelerate the initiation and progression of multiple cancers [26, 27].”
BackgroundBanton, M. I., Bus, J. S., Collins, J. J., Delzell, E., Gelbke, H.-P., Kester, J. E., Moore, M. M., Waites, R., & Sarang, S. S. (2019) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2019.1633718 · Cited by 89 · see citing works
Manevski, M., Muthumalage, T., Devadoss, D., Sundar, I. K., Wang, Q., Singh, K. P., Unwalla, H. J., Chand, H. S., & Rahman, I. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101443 · Cited by 83 · see citing works
Chen, J., Liu, A., Lin, Z., Wang, B., Chai, X., Chen, S., Lu, W., Zheng, M., Cao, T., Zhong, M., et al. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.04.007 · Cited by 88 · see citing works
Induction of Accelerated Aging in a Mouse Model
Cai, N., Wu, Y., & Huang, Y. Y. (2022) · Cells · doi:10.3390/cells11091418 · Cited by 92 · see citing works
In vivo flow cytometry reveals a circadian rhythm of circulating tumor cells
Zhu, X., Suo, Y., Fu, Y., Zhang, F., Ding, N., Pang, K., Xie, C., Weng, X., Tian, M., He, H., et al. (2021) · Light Science & Applications · doi:10.1038/s41377-021-00542-5 · Cited by 83 · see citing works
Peng, F., Lü, J., Su, K., Liu, X., Luo, H., He, B., Wang, C., Zhang, X., An, F., Lv, D., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.04.018 · Cited by 88 · see citing works
Ng, S. R., Rideout, W. M., Akama‐Garren, E. H., Bhutkar, A. J., Mercer, K. L., Schenkel, J. M., Bronson, R. T., & Jacks, T. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821893117 · Cited by 76 · see citing works
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Wang, Z., Su, G.-H., Dai, Z., Meng, M., Zhang, H., Fan, F., Liu, Z., Zhang, L., Weygant, N., He, F., et al. (2021) · Cell Proliferation · doi:10.1111/cpr.12988 · Cited by 80 · see citing works
Opposite Carcinogenic Effects of Circadian Clock Gene BMAL1
Korkmaz, T., Aygenli, F., Emisoglu, H., Özcelik, G., Canturk, A., Yilmaz, S., & Öztürk, N. (2018) · Scientific Reports · doi:10.1038/s41598-018-34433-4 · Cited by 79 · see citing works
Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis
Yang, C., Wu, J., Liu, X., Wang, Y., Liu, B., Chen, X., Wu, X., Yan, D., Han, L., Liu, S., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0493 · Cited by 53 · see citing works
“has been proposed as a tumor suppressor (24, 29, 48, 49).”
BackgroundThe role of circadian clock genes in tumors
Li, H.-X. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s203144 · Cited by 77 · see citing works
Li, K., Zhang, Y., Liu, X., Liu, Y., Gu, Z., Cao, H., Dickerson, K. E., Chen, M., Chen, W., Shao, Z., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1128 · Cited by 58 · see citing works
“Emerging evidence in several in vivo models also points to important roles of other core circadian genes in tumorigenesis (39, 40).”
BackgroundGenetic variation of clock genes and cancer risk: a field synopsis and meta-analysis
Benna, C., Helfrich‐Förster, C., Rajendran, S., Monticelli, H., Pilati, P., Nitti, D., & D, S. M. M. (2017) · Oncotarget · doi:10.18632/oncotarget.15074 · Cited by 71 · see citing works
“Sleep deprivation, jet-lag, shiftwork involving nightshifts and unnatural light exposure are all potential causes of circadian disruption which has been correlated, in different epidemiological studies and in laboratory studies, with diseases such as obesity, diabetes, depression and cancer [5-15].”
ResultCircadian molecular clock disruption in chronic pulmonary diseases
Giri, A., Wang, Q., Rahman, I., & Sundar, I. K. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.04.002 · Cited by 70 · see citing works
Circadian clock, carcinogenesis, chronochemotherapy connections
Yang, Y., Lindsey‐Boltz, L. A., Vaughn, C. M., Selby, C. P., Cao, X., Liu, Z., Hsu, D. S., & Sancar, A. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101068 · Cited by 69 · see citing works
“deletions were subjected to chronic jet lag, they exhibited higher tumor incidence and progression compared with controls (44).”
BackgroundConnecting the Metabolic and Immune Responses to Cancer
Flint, T. R., Fearon, D. T., & Janowitz, T. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.001 · Cited by 70 · see citing works
Kim, E., Kim, Y.-J., Ji, Z., Kang, J. M., Wirianto, M., Paudel, K. R., Smith, J. A., Ono, K., Kim, J.-A., Eckel‐Mahan, K. L., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04826-5 · Cited by 67 · see citing works
Why Lungs Keep Time: Circadian Rhythms and Lung Immunity
Nosal, C. R., Ehlers, A., & Haspel, J. A. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034602 · Cited by 65 · see citing works
“Over the long term, chronic circadian disruption in humans and model organisms is associated with increased rates of heart disease, metabolic syndrome, and cancer (including lung cancer) (17, 18).”
BackgroundMajor roles of the circadian clock in cancer
Huang, C. L., Zhang, C., Cao, Y., Li, J., & Bi, F. (2023) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2022.0474 · Cited by 61 · see citing works
Jiang, W., Zhao, S., Shen, J., Guo, L., Sun, Y., Zhu, Y., Ma, Z., Zhang, X., Hu, Y., Xiao, W., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0233-y · Cited by 62 · see citing works
Melatonin: A Molecule for Reducing Breast Cancer Risk
González-González, A., Mediavilla, M., & Sánchez‐Barceló, E. J. (2018) · Molecules · doi:10.3390/molecules23020336 · Cited by 62 · see citing works
“Circadian rhythm disruption induces alterations in one hallmark of cancer, cell division, thus contributing to cancer progression, and the pharmacological modulation of proteins related to clock genes is being considered as a possible strategy for cancer treatment [64,65].”
BackgroundCLOCK and BMAL1 stabilize and activate RHOA to promote F-actin formation in cancer cells
Ma, T., Zhang, Z.-W., Lu, Y.-L., Zhang, Y., Tao, D., Liu, Y.-Q., & Ma, Y. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0156-4 · Cited by 59 · see citing works
Neural function of Bmal1: an overview
Zheng, Y., Pan, L., Wang, F., Yan, J., Wang, T., Xia, Y., Yao, L., Deng, K., Zheng, Y., Xia, X., et al. (2023) · Cell & Bioscience · doi:10.1186/s13578-022-00947-8 · Cited by 60 · see citing works
“For example, it has been demonstrated to inhibit cell growth in some cancers, such as neuroblastoma [35], tongue squamous cell carcinoma [36], spontaneous hepatocellular carcinoma [37] and lung tumors [38].”
BackgroundInterplay between circadian clock and viral infection
Zhuang, X. A., Rambhatla, S. B., Lai, A. G., & McKeating, J. A. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1592-7 · Cited by 58 · see citing works
Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras -driven lung cancer
Pariollaud, M., Ibrahim, L. H., Irizarry, E., Mello, R. M., Chan, A. B., Altman, B. J., Shaw, R. J., Bollong, M. J., Wiseman, R. L., & Lamia, K. A. (2022) · Science Advances · doi:10.1126/sciadv.abo1123 · Cited by 57 · see citing works
Liu, J., Wang, C., Cheng, T.-Y., Rixiati, Y., Ji, C., Deng, M., Yao, S., Yuan, L., Zhao, Y., Shen, T., et al. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.02.008 · Cited by 58 · see citing works
Ticking time bombs: connections between circadian clocks and cancer
Lamia, K. A. (2017) · F1000Research · doi:10.12688/f1000research.11770.1 · Cited by 56 · see citing works
Wang, Q., Sundar, I. K., Lucas, J. H., Muthumalage, T., & Rahman, I. (2021) · JCI Insight · doi:10.1172/jci.insight.145200 · Cited by 56 · see citing works
“Interestingly, Per2 also served as a tumor suppressor, targeting cell proliferation and cell-cycle progression (18).”
Huang, Q., Hu, B., Ping, Z., Yuan, Y., Yue, S., Chen, X., Liang, J., Tang, Z., & Zhang, B. (2025) · Molecular Cancer · doi:10.1186/s12943-024-02219-0 · Cited by 63 · see citing works
Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis
Wang, Y., Narasimamurthy, R., Qu, M., Shi, N., Guo, H.-D., Xue, Y., & Barker, N. (2024) · Nature Cancer · doi:10.1038/s43018-024-00759-4 · Cited by 61 · see citing works
Escape from senescence: molecular basis and therapeutic ramifications
Evangelou, K., Belogiannis, K., Papaspyropoulos, A., Petty, R., & Gorgoulis, V. G. (2023) · The Journal of Pathology · doi:10.1002/path.6164 · Cited by 55 · see citing works
“There is substantial evidence linking the circadian clock with the cell-cycle machinery and its disruption has been associated with various pathologies, including cancer [88,89].”
BackgroundSirtuins and the circadian clock interplay in cardioprotection: focus on sirtuin 1
Soni, S. K., Basu, P., Singaravel, M., Sharma, R., Pandi-Perumal, S. R., Cardinali, D. P., & Reiter, R. J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03713-6 · Cited by 53 · see citing works
The Relationship between Circadian Rhythm and Cancer Disease
Munteanu, C., Turti, S., Achim, L., Muresan, R., Souca, M., Prifti, E., Mârza, S. M., & Papuc, I. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115846 · Cited by 60 · see citing works
“Specifically, changes in circadian rhythms caused by genetics and environmental factors significantly affect the expression and function of several suppressor genes and cancer genes in the host tissues and the tumor, favoring the development and proliferation of cancer cells [108].”
BackgroundThe MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape
Wang, L.-H., Aberin, M. A. E., Wu, S., & Wang, S.-P. (2021) · Biochemical Society Transactions · doi:10.1042/bst20191164 · Cited by 53 · see citing works
Zhou, J., Li, X., Zhang, M., Gong, J., Li, Q., Shan, B., Wang, T., Zheng, T., Zheng, T., & Li, X. (2020) · Cancer Medicine · doi:10.1002/cam4.2834 · Cited by 39 · see citing works
Genome‐wide effect of pulmonary airway epithelial cell–specific Bmal1 deletion
Zhang, Z., Hunter, L., Wu, G., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201801682r · Cited by 52 · see citing works
- Authors
- Papagiannakopoulos, T., Bauer, M. R., Davidson, S. M., Heimann, M., Subbaraj, L., Bhutkar, A., Bartlebaugh, J., Vander Heiden, M. G., & Jacks, T.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 24
- Issue
- 2
- Pages
- 324-331
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5367626
- OpenAlex
- W2505703250
- Cited by
- 557
- References
- 46
- Citations by year
- 2026: 42 · 2025: 62 · 2024: 65 · 2023: 73 · 2022: 68 · 2021: 64 · 2020: 72 · 2019: 41 · 2018: 37 · 2017: 24 · 2016: 8 · 2013: 1
- FWCI
- 23.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Howard Hughes Medical Institute
- American Cancer Society
- Lung Cancer Research Foundation
- Hope Funds for Cancer Research
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Cancer Institute (P01CA042063, R01CA168653, P30CA014051)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- circadian rhythm disruption, lung carcinogenesis, lung adenocarcinoma, jet lag, shift work, clock genes, Per2, Bmal1, c-Myc, tumor progression, tumor suppression, cell proliferation, metabolic dysfunction, genetically engineered mouse models
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Animals, Cell Transformation, Neoplastic, Circadian Rhythm, Glucose, Glutamine, Humans, Lung, Lung Neoplasms, Mice, Inbred C57BL, Mutation, Proto-Oncogene Proteins c-myc, Jet Lag Syndrome, Cell Proliferation, Period Circadian Proteins, Carcinogenesis, Cellular Reprogramming
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