BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
Open accessPublished version of a preprint
Abstract
Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here, we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell–mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program. Significance: This study reveals how cells undergoing oncogene-induced senescence acquire a distinctive enhancer landscape that includes formation of super-enhancers adjacent to immune-modulatory genes required for paracrine immune activation. This process links BRD4 and super-enhancers to a tumor-suppressive immune surveillance program that can be disrupted by small molecule inhibitors of the bromo and extra terminal domain family of proteins. Cancer Discov; 6(6); 612–29. ©2016 AACR. See related commentary by Vizioli and Adams, p. 576. This article is highlighted in the In This Issue feature, p. 561
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Genome-wide analysis of H3K4me3, H3K27me3 and H3K27ac in senescent cells reveals dynamic acquisition and depletion of large-scale chromatin domains proposed to regulate key senescence downstream effectors.
“Genome-wide analysis of H3 Lys4 trimethylation, H3 Lys27 trimethylation and H3 Lys27 acetylation in senescent cells has also revealed the dynamic acquisition and depletion of large-scale chromatin domains that have been proposed to regulate the expression of key senescence downstream effectors68–72”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [71]
The Results sections on enhancer remodeling and the SASP transcriptional profile report genome-wide H3K27ac changes in senescent IMR90 cells, including gains and losses at super-enhancers associated with senescence-related gene expression. The Methods describe analysis of H3K27ac and H3K4me1, but not the claimed H3K4me3 or H3K27me3 analyses. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBRD4 supports the proper execution of cellular senescence and unexpectedly behaves as a tumour suppressor.
“BRD4 contributes to the proper execution of cellular senescence and acts, unexpectedly, as a tumour suppressor.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [71]
Chemical or genetic inactivation of BRD4 reduces the SASP, limits immune-mediated clearance in OIS, and may leave damaged cells that can escape senescence.
“Indeed, chemical and genetic inactivation of BRD4 blunts the SASP, limits OIS immune-mediated cell clearance and may thus fail to remove damaged cells that are prone to senescence escape71.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [71]
MacroH2A1, HMGB2, MLL1 and BRD4 regulate SASP factor gene expression in response to DNA damage.
“Other epigenetic regulators, such as macroH2A1, high mobility group box 2 (HMGB2), mixed‐lineage leukemia 1 (MLL1) and bromodomain‐containing protein 4 (BRD4), have been demonstrated as regulators of SASP factor gene expression in response to DNA damage.52, 53, 54, 55”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [55]
BRD4 inactivation via shRNA or BET inhibitors has been shown to repress SASP gene expression in oncogene-induced senescent cells, suggesting the possibility of senescence without the SASP.
“BRD4 inactivation via shRNA or BET inhibitors has been shown to repress SASP gene expression in oncogene-induced senescent cells [29], suggesting the possibility of senescence without the SASP [30].”
From Ensemble of Time-Evolving SASP Gene Sets Identifies IGFBP7 and CDKN1A as a Potential Marker Pair for Senescent Fibroblast Subpopulations Across Tissues (2026) · cites this paper as [29]
Other epigenetic regulators such as BRD4, MLL1, HMGB2, macroH2A1, and GATA4 are involved in regulating SASP.
“Other epigenetic regulators such as BRD4 (Tasdemir et al., 2016), MLL1 (Capell et al., 2016), HMGB2 (Guerrero and Gil, 2016), histone variant macroH2A1 (Chen et al., 2015), and GATA4 (Kang et al., 2015) are also involved in regulating SASP.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Tasdemir et al., 2016
The SASP is thought to instigate immune clearance of damaged/stressed cells.
“The SASP is thought to instigate immune clearance of the damaged/stressed cells (Tasdemir et al., 2016), but the immediate negative consequence is the potential to drive local tissue damage and systemic chronic sterile inflammation (Franceschi and Campisi, 2014).”
From DNA damage-how and why we age? (2021) · cites this paper as Tasdemir et al., 2016
The chromatin reader BRD4 is recruited to super-enhancer elements adjacent to key SASP genes and is required for their expression.
“More directly, the chromatin reader BRD4 is recruited to super-enhancer elements that form adjacent to key SASP genes and is required for their expression [170].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [170]
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“The senescence-induced cell-cycle program involves vast changes in the heterochromatin organization leading to transcriptional repression (20, 21), whereas the gene activation program can involve recruitment of key transcriptional activators (31, 40, 59).”
Influential(2003) · PubMed · Cited by 608 · see citing works
Brd4 Coactivates Transcriptional Activation of NF-κB via Specific Binding to Acetylated RelA
Huang, B., Yang, X., Zhou, M., Ozato, K., & Chen, L. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01365-08 · Cited by 586 · see citing works
Jaguin, M., Houlbert, N., Fardel, O., & Lecureur, V. (2013) · Cellular Immunology · doi:10.1016/j.cellimm.2013.01.010 · Cited by 520 · cited 1× · see citing works
“Human macrophages were harvested following an 18-hour incubation with the indicated CM and processed for qRT-PCR analysis of previously described M1 or M2 polarization markers (75, 76).”
MethodA negative feedback signaling network underlies oncogene-induced senescence
Courtois-Cox, S., Genther Williams, S. M., Reczek, E. E., Johnson, B. W., McGillicuddy, L. T., Johannessen, C. M., Hollstein, P. E., MacCollin, M., & Cichowski, K. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.003 · Cited by 501 · cited 1× · see citing works
“S3E, top plot), which have been previously implicated in senescence (46, 47).”
Shi, J., Wang, Y., Zeng, L., Wu, Y., Deng, J., Zhang, Q., Lin, Y., Li, J., Kang, T., Tao, M., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.01.028 · Cited by 483 · see citing works
Belkina, A. C., Nikolajczyk, B. S., & Denis, G. V. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202838 · Cited by 421 · cited 1× · see citing works
“Besides their novel role in senescence surveillance as described above, BET proteins are crucial for the inflammatory response of various immune cells (41, 58).”
Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model
Burd, C. E., Sorrentino, J. A., Clark, K. S., Darr, D. B., Krishnamurthy, J., Deal, A. M., Bardeesy, N., Castrillon, D. H., Beach, D. H., & Sharpless, N. E. (2013) · Cell · doi:10.1016/j.cell.2012.12.010 · Cited by 419 · see citing works
Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W., & Raulet, D. H. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20130783 · Cited by 414 · see citing works
Self-citationMany roads lead to oncogene-induced senescence
Courtois-Cox, S., Jones, S. L., & Cichowski, K. (2008) · Oncogene · doi:10.1038/sj.onc.1210950 · Cited by 397 · cited 1× · see citing works
“In this model, senescence is triggered by the introduction of oncogenic HRASV12, which provokes a proliferative burst followed by induction of p53, p16Ink4a, cellcycle exit, and the production of SA-β-gal and SASP (19, 44).”
Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence
Chicas, A., Wang, X., Zhang, C., McCurrach, M., Zhao, Z., Mert, O., Dickins, R. A., Narita, M., Zhang, M., & Lowe, S. W. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.023 · Cited by 388 · cited 4× · see citing works
“As additional controls, we inactivated classic tumor suppressor genes, such as p53 and RB, known to direct the gene repression program leading to a permanent cell-cycle arrest (20), as well as the cell-cycle regulators p21 and p16 (CDKN1A and CDKN2A), which when inhibited in combination can bypass senescence in IMR90…”
InfluentialSelf-citationCritical pathways in cellular senescence and immortalization revealed by gene expression profiling
Fridman, A. L., & Tainsky, M. A. (2008) · Oncogene · doi:10.1038/onc.2008.213 · Cited by 385 · cited 1× · see citing works
“This signature is similar to that produced by our laboratory using microarray technology (26, 49) and to those in previously published reports (54, 55).”
Phospho Switch Triggers Brd4 Chromatin Binding and Activator Recruitment for Gene-Specific Targeting
Wu, S.-Y., Lee, A.-Y., Lai, H., Zhang, H., & Chiang, C. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.12.006 · Cited by 350 · cited 1× · see citing works
“Moreover, although BRD4 had no marked impact on p53 transcriptional profiles in our system, phosphorylated BRD4 can act as a transcriptional coactivator for p53 in certain cell types (72).”
Roe, J., Mercan, F., Rivera, K. D., Pappin, D., & Vakoc, C. R. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.04.011 · Cited by 332 · cited 1× · see citing works
“ChIP-Seq and Bioinformatics Analysis ChIP-Seq was performed as previously described (65).”
MethodSelf-citationCoppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302 · cited 1× · see citing works
“Most interestingly, SE activation resulted in induction of genes related to cytokine and growth factor activity, which include essential components of the SASP (24, 26) and also categorically distinguished senescent cells from growth-arrested quiescent counterparts.”
Cellular senescence in vivo: a barrier to tumorigenesis
Prieur, A., & Peeper, D. S. (2008) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2008.01.007 · Cited by 260 · cited 1× · see citing works
“For example, cellular senescence can restrict tumorigenesis (4, 5) and modulate chemotherapy responses (6–8), and may exert a primordial role in wound healing, tissue remodeling, and repair (9–13).”
Granule exocytosis mediates immune surveillance of senescent cells
Sagiv, A., Biran, A., Yon, M., Simon, J., Lowe, S. W., & Krizhanovsky, V (2013) · Oncogene · doi:10.1038/onc.2012.206 · Cited by 240 · see citing works
Self-citationBRD4 is a novel therapeutic target for liver fibrosis
Ding, N., Hah, N., Yu, R. T., Sherman, M. H., Benner, C., Leblanc, M., He, M., Liddle, C., Downes, M., & Evans, R. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1522163112 · Cited by 211 · cited 1× · see citing works
“Moreover, analyses of all H3K27Ac-marked SEs identified additional TFs such as SMAD3, C/EBPβ, or the GATA family, previously linked to senescence (31, 51, 52) as well as to liver fibrosis (67), pointing to both specific and common regulatory mechanisms driving enhancer-mediated secretory pathway activation in differen…”
Chen, H., Ruiz, P. D., McKimpson, W. M., Novikov, L., Kitsis, R. N., & Gamble, M. J. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.011 · Cited by 205 · see citing works
Bolden, J. E., Tasdemir, N., Dow, L. E., van Es, J. H., Wilkinson, J. E., Zhao, Z., Clevers, H. C., & Lowe, S. W. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.025 · Cited by 188 · cited 1× · see citing works
“dedifferentiation in human breast cancer cells and cells from patients with premature aging syndrome (69, 70), and promotes hyperproliferation in the murine epidermis (71).”
Self-citationMLL1 is essential for the senescence-associated secretory phenotype
Capell, B. C., Drake, A. M., Zhu, J., Shah, P. P., Dou, Z., Dorsey, J., Simola, D. F., Donahue, G., Sammons, M., Rai, T. S., et al. (2016) · Genes & Development · doi:10.1101/gad.271882.115 · Cited by 156 · cited 1× · see citing works
“The senescence-induced cell-cycle program involves vast changes in the heterochromatin organization leading to transcriptional repression (20, 21), whereas the gene activation program can involve recruitment of key transcriptional activators (31, 40, 59).”
Toll like receptor signaling in “inflammaging”: microRNA as new players
Olivieri, F., Rippo, M. R., Prattichizzo, F., Babini, L., Graciotti, L., Recchioni, R., & Procopio, A. D. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-11 · Cited by 137 · see citing works
Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages
Joshi, A., Oak, S. R., Hartigan, A. J., Finn, W. G., Kunkel, S. L., Duffy, K. E., Das, A., & Hogaboam, C. M. (2010) · BMC Immunology · doi:10.1186/1471-2172-11-52 · Cited by 135 · cited 1× · see citing works
“Human macrophages were harvested following an 18-hour incubation with the indicated CM and processed for qRT-PCR analysis of previously described M1 or M2 polarization markers (75, 76).”
MethodMolecular signature of oncogenic ras-induced senescence
Mason, D. X., Jackson, T. J., & Lin, A. W. (2004) · Oncogene · doi:10.1038/sj.onc.1208172 · Cited by 127 · cited 1× · see citing works
“This signature is similar to that produced by our laboratory using microarray technology (26, 49) and to those in previously published reports (54, 55).”
Menck, K., Behme, D., Pantke, M., Reiling, N., Binder, C., Pukrop, T., & Klemm, F. (2014) · Journal of Visualized Experiments · doi:10.3791/51554 · Cited by 99 · cited 1× · see citing works
“Human macrophages were generated from monocytes isolated from buffy coats from healthy human blood donors (New York Blood Center) and differentiated in Teflon-coated cell culture bags in the presence of human CSF1 (R&D Systems), as previously described (74).”
Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model.
Vijayachandra, K., Lee, J., & Glick, A. B. (2003) · PubMed · Cited by 95 · see citing works
The BET Family Member BRD4 Interacts with OCT4 and Regulates Pluripotency Gene Expression
Wu, T., Pinto, H. B., Kamikawa, Y. F., & Donohoe, M. E. (2015) · Stem Cell Reports · doi:10.1016/j.stemcr.2015.01.012 · Cited by 86 · see citing works
Alsarraj, J., Walker, R. C., Webster, J. D., Geiger, T. R., Crawford, N. P. S., Simpson, R. J., Ozato, K., & Hunter, K. W. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-4417 · Cited by 81 · cited 1× · see citing works
“dedifferentiation in human breast cancer cells and cells from patients with premature aging syndrome (69, 70), and promotes hyperproliferation in the murine epidermis (71).”
Fernández, P., Scaffidi, P., Markert, E. K., Lee, J.-H., Rane, S. G., & Misteli, T. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.069 · Cited by 67 · cited 1× · see citing works
“dedifferentiation in human breast cancer cells and cells from patients with premature aging syndrome (69, 70), and promotes hyperproliferation in the murine epidermis (71).”
Altered senescence, apoptosis, and DNA damage response in a mutant p53 model of accelerated aging
Hinkal, G. W., Gatza, C. E., Parikh, N., & Donehower, L. A. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2009.01.001 · Cited by 45 · cited 1× · see citing works
“Besides its role in cancer, the SASP response also contributes to tissue repair (10, 13), fibrosis (9, 66), and aging (73), and, in principle, BET inhibitors could provide strategies to modulate the SASP response and these processes at the organismal level.”
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Hallmarks of Cellular Senescence
Hernandez-Segura, A., Nehme, J., & Demaria, M. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.02.001 · Cited by 2,605 · see citing works
“Finally, the 3D arrangement of the chromatin also influences the transcription of SASP genes [64], while chromatin-bound HMGB2 fine tunes SASP expression by avoiding heterochromatin spreading [65].”
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277 · see citing works
Aging and aging-related diseases: from molecular mechanisms to interventions and treatments
Guo, J., Huang, X., Dou, L., Yan, M., Shen, T., Tang, W., & Li, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01251-0 · Cited by 1,834 · see citing works
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
“Other epigenetic regulators such as BRD4 (Tasdemir et al., 2016), MLL1 (Capell et al., 2016), HMGB2 (Guerrero and Gil, 2016), histone variant macroH2A1 (Chen et al., 2015), and GATA4 (Kang et al., 2015) are also involved in regulating SASP.”
BackgroundCytoplasmic chromatin triggers inflammation in senescence and cancer
Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., et al. (2017) · Nature · doi:10.1038/nature24050 · Cited by 1,335 · see citing works
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · see citing works
“BRD4, a member of the BET family, is a chromatin reader whose role in the activation of the SASP and in the subsequent immune clearance is well documented, and its inhibition with JQ1 or analogs impairs both processes in a model of NRAS driven OIS in vitro and in vivo (315).”
BackgroundSenescent cells: an emerging target for diseases of ageing
Childs, B. G., Gluscevic, M., Baker, D. J., Laberge, R.-M., Marquess, D., Dananberg, J., & van Deursen, J. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.116 · Cited by 1,284 · see citing works
Senescence and aging: Causes, consequences, and therapeutic avenues
McHugh, D., & Gil, J. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201708092 · Cited by 1,233 · see citing works
“There is also a global remodeling of enhancers in senescent cells, and the recruitment of BRD4 to superenhancers adjacent to SASP genes is needed for their induction (Tasdemir et al., 2016).”
BackgroundMechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · see citing works
“Perhaps more relevant, SASP induction requires the recruitment of BRD4 to senescence-activated super-enhancers that lie adjacent to SASP genes (90).”
Senescence and the SASP: many therapeutic avenues
Birch, J., & Gil, J. (2020) · Genes & Development · doi:10.1101/gad.343129.120 · Cited by 1,177 · see citing works
“During OIS, enhancer landscapes are remodeled with recruitment of the bromodomain and extra-terminal (BET) family protein BRD4 to superenhancer elements adjacent to SASP genes (Tasdemir et al. 2016).”
BackgroundMethodSenolytic CAR T cells reverse senescence-associated pathologies
Amor, C., Feucht, J., Leibold, J., Ho, Y.-J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., et al. (2020) · Nature · doi:10.1038/s41586-020-2403-9 · Cited by 1,098 · see citing works
Self-citationcGAS is essential for cellular senescence
Yang, H., Wang, H., Ren, J., Chen, Q., & Chen, Z. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705499114 · Cited by 1,009 · see citing works
Unmasking senescence: context-dependent effects of SASP in cancer
Faget, D. V., Ren, Q., & Stewart, S. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0156-2 · Cited by 863 · see citing works
The senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948 · see citing works
“In OIS, global enhancer remodelling was identified, and bromodomain-containing protein 4 (BRD4) was shown to be recruited to senescence-activated enhancers, contributing to the expression of SASP factors without interfering with growth arrest 109 .”
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Epigenetic regulation of aging: implications for interventions of aging and diseases
Kang, W., Liu, H., Hu, Q., Wang, L., Liu, J., Zheng, Z., Zhang, W., Ren, J., Zhu, F., & Liu, G. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01211-8 · Cited by 694 · see citing works
“Interestingly, abundant H3K4me1 marks are displayed in replicatively senescent IMR90 cells at the senescence-associated secretory phenotype (SASP)-associated super-enhancer loci, which also show substantial H3K27ac marks and BRD4 binding.(96,99) Recent studies also demonstrated that aging-mediated changes in H3K27ac a…”
BackgroundThe dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588 · see citing works
The senescence-associated secretory phenotype and its regulation
Lopes-Paciencia, S., Saint-Germain, E., Rowell, M.-C., Ruiz, A. F., Kalegari, P., & Ferbeyre, G. (2019) · Cytokine · doi:10.1016/j.cyto.2019.01.013 · Cited by 601 · see citing works
Molecular mechanisms linking exercise to cancer prevention and treatment
Hojman, P., Gehl, J., Christensen, J. F., & Pedersen, B. K. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.015 · Cited by 600 · see citing works
Targeting CDK4 and CDK6 in cancer
Goel, S., Bergholz, J. S., & Zhao, J. J. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00456-3 · Cited by 554 · see citing works
Strategies for targeting senescent cells in human disease
Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021) · Nature Aging · doi:10.1038/s43587-021-00121-8 · Cited by 501 · see citing works
Loo, T. M., Kamachi, F., Watanabe, Y., Yoshimoto, S., Kanda, H., Arai, Y., Nakajima-Takagi, Y., Iwama, A., Koga, T., Sugimoto, Y., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0932 · Cited by 478 · see citing works
BET Proteins as Targets for Anticancer Treatment
Stathis, A., & Bertoni, F. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0605 · Cited by 463 · see citing works
“Finally, a tumor-suppressor role for BET proteins has also been reported in which their inhibition would result in a reduced immune surveillance (86) and reduced capacity of healthy cells to counteract the neoplastic transformation process (87).”
BackgroundNK cell–mediated cytotoxicity contributes to tumor control by a cytostatic drug combination
Ruscetti, M., Leibold, J., Bott, M. J., Fennell, M., Kulick, A., Salgado, N. R., Chen, C.-C., Ho, Y.-J., Sanchez-Rivera, F. J., Feucht, J., et al. (2018) · Science · doi:10.1126/science.aas9090 · Cited by 415 · see citing works
Self-citationSenescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer
Ruscetti, M., Morris, J. P., Mezzadra, R., Russell, J., Leibold, J., Romesser, P. B., Simon, J., Kulick, A., Ho, Y.-J., Fennell, M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.03.008 · Cited by 424 · see citing works
“, 2003), and a nuclear factor κB (NF-κB)-regulated gene activation program that induces expression of secreted factors that can influence the microenvironment (Chien et al., 2011; Lesina et al., 2016; Tasdemir et al., 2016).”
Self-citationNAD+ metabolism governs the proinflammatory senescence-associated secretome
Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., Aird, K. M., Iwasaki, O., Kossenkov, A. V., Schultz, D., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0287-4 · Cited by 402 · see citing works
Cai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022) · Science China Life Sciences · doi:10.1007/s11427-022-2161-3 · Cited by 436 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
“More directly, the chromatin reader BRD4 is recruited to super-enhancer elements that form adjacent to key SASP genes and is required for their expression [170].”
BackgroundDNA damage-how and why we age?
Yousefzadeh, M., Henpita, C., Vyas, R., Soto-Palma, C., Robbins, P., & Niedernhofer, L. (2021) · eLife · doi:10.7554/elife.62852 · Cited by 399 · see citing works
“The SASP is thought to instigate immune clearance of the damaged/stressed cells (Tasdemir et al., 2016), but the immediate negative consequence is the potential to drive local tissue damage and systemic chronic sterile inflammation (Franceschi and Campisi, 2014).”
BackgroundBao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 389 · see citing works
Self-citationTakahashi, A., Loo, T. M., Okada, R., Kamachi, F., Watanabe, Y., Wakita, M., Watanabe, S., Kawamoto, S., Miyata, K., Barber, G. N., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03555-8 · Cited by 350 · see citing works
Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes
Thompson, P. J., Shah, A., Ntranos, V., Van Gool, F., Atkinson, M., & Bhushan, A. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.021 · Cited by 353 · see citing works
Super-Enhancer-Driven Transcriptional Dependencies in Cancer
Sengupta, S., & George, R. E. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.03.006 · Cited by 349 · see citing works
“Oncogenic Nras expression in mouse liver iBET (BRD4) Reduced expression of [320_TD$DIFF]SEdriven genes involved in SASP Decreased clearance of oncogenic senescent cells [81]”
BackgroundInfluentialTherapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
Prasanna, P. G. S., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., Xi, D., Zheng, G., van Deursen, J., Goronzy, J. J., et al. (2021) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djab064 · Cited by 351 · see citing works
“inhibitor rapamycin (72), JAK1/2 inhibitor ruxolitinib (73), and BET inhibitor JQ1 (74) may also be useful, the focus has been on senolytics.”
BackgroundSelf-citationRole of immune cells in the removal of deleterious senescent cells
Kale, A., Sharma, A., Stolzing, A., Desprez, P.-Y., & Campisi, J. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00187-9 · Cited by 351 · see citing works
“A role for the SASP in immune clearance of senescent cells was further highlighted by the finding that the epigenetic regulator BRD4, which dictates the enhancer and superenhancer landscape of SASP genes, determines the ability of the SASP to promote immune clearance of senescent cells [46].”
BackgroundCellular senescence in renal ageing and disease
Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J., & van Deursen, J. M. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.183 · Cited by 345 · see citing works
Watanabe, S., Kawamoto, S., Ohtani, N., & Hara, E. (2017) · Cancer Science · doi:10.1111/cas.13184 · Cited by 321 · see citing works
A gene–environment-induced epigenetic program initiates tumorigenesis
Alonso‐Curbelo, D., Ho, Y.-J., Burdziak, C., Mååg, J. L. V., Morris, J. P., Chandwani, R., Chen, H.-A., Tsanov, K. M., Barriga, F. M., Luan, W., et al. (2021) · Nature · doi:10.1038/s41586-020-03147-x · Cited by 306 · see citing works
Self-citationHogg, S. J., Vervoort, S. J., Deswal, S., Ott, C. J., Li, J., Cluse, L. A., Beavis, P. A., Darcy, P. K., Martin, B. P., Spencer, A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.011 · Cited by 308 · see citing works
“, 2010) and more recently genes such as IL1A, IL1B, and IL8 that are activated as part of the senescenceassociated secretory response (Tasdemir et al., 2016).”
BackgroundResultThe BET family in immunity and disease
Wang, N., Wu, R., Tang, D., & Kang, R. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00384-4 · Cited by 295 · see citing works
“BRD4 is recruited to newly activated SEs adjacent to key SASP-related genes and mediates downstream paracrine signaling, thereby contributing to tumor-suppressive immune surveillance.(150) Therefore, changes in the BRD4 pathway allow tumors to evade immune surveillance and to excessively proliferate, leading to their…”
BackgroundCuollo, L., Antonangeli, F., Santoni, A., & Soriani, A. (2020) · Biology · doi:10.3390/biology9120485 · Cited by 291 · see citing works
p21 produces a bioactive secretome that places stressed cells under immunosurveillance
Sturmlechner, I., Zhang, C., Sine, C. C., van Deursen, E.-J., Jeganathan, K. B., Hamada, N., Grasic, J., Friedman, D., Stutchman, J. T., Can, I., et al. (2021) · Science · doi:10.1126/science.abb3420 · Cited by 295 · see citing works
Ito, T., Teo, Y. V., Evans, S. A., Neretti, N., & Sedivy, J. M. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.002 · Cited by 265 · see citing works
“In contrast, senescence leads to an increase in histone H3 lysine 27 acetyl (H3K27ac) at enhancers adjacent to SASP genes (Tasdemir et al., 2016).”
AP-1 imprints a reversible transcriptional programme of senescent cells.
Martínez-Zamudio, R. I., Roux, P.-F., de Freitas, J. A. N. L. F., Robinson, L., Doré, G., Sun, B., Belenki, D., Milanovic, M., Herbig, U., Schmitt, C. A., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0529-5 · Cited by 236 · see citing works
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“PCA of exon inclusion levels of previously published datasets (Tasdemir et al., 2016) suggested that alternative splicing occurring in RASinduced senescence is likely due to both senescence induction and RAS activation, the latter being the strongest contributor (Figure S7B).”
BackgroundRepression of BET activity sensitizes homologous recombination–proficient cancers to PARP inhibition
Yang, L., Zhang, Y., Shan, W., Hu, Z., Yuan, J., Pi, J., Wang, Y., Fan, L., Tang, Z., Li, C., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal1645 · Cited by 243 · see citing works
Molecular mechanisms of renal aging
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“However, the recent finding that bromodomain-containing protein 4 inhibition interferes with immune cell–mediated targeting and elimination of senescent cells points to the possibility to combat SASP more specifically.(148)”
BackgroundSenescence Rewires Microenvironment Sensing to Facilitate Antitumor Immunity
Chen, H.-A., Ho, Y.-J., Mezzadra, R., Adrover, J. M., Smolkin, R. M., Zhu, C., Woess, K., Bernstein, N., Schmitt, G., Fong, L. E., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0528 · Cited by 230 · see citing works
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Cellular senescence: Immunosurveillance and future immunotherapy
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“The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.”
BackgroundAmor, C., Fernández-Maestre, I., Chowdhury, S., Ho, Y.-J., Nadella, S., Graham, C., Carrasco, S. E., Nnuji-John, E., Feucht, J., Hinterleitner, C., et al. (2024) · Nature Aging · doi:10.1038/s43587-023-00560-5 · Cited by 241 · see citing works
“Importantly, when senescent cells present in these tissues were identified using two independent transcriptomic signatures of senescence 17,24 , we observed that the main senescent cell types present in aged tissues were distinct: endothelial and myeloid cells in the liver (Fig.”
BackgroundMethodInfluentialSelf-citationClassical and Nonclassical Intercellular Communication in Senescence and Ageing
Fafián‐Labora, J., & O’Loghlen, A. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.05.003 · Cited by 230 · see citing works
Senescent alveolar macrophages promote early-stage lung tumorigenesis
Prieto, L. I., Sturmlechner, I., Graves, S. I., Zhang, C., Goplen, N. P., Yi, E. S., Sun, J., Li, H., & Baker, D. J. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.05.006 · Cited by 212 · see citing works
NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates
Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., Zhang, X., Liu, N., Yan, L., Deng, Y., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.add1951 · Cited by 214 · see citing works
“The human lung fibroblast cell lines IMR90 (catalog number CCL186) and WI38 (catalog number CCL-75) were purchased from the American Type Culture Collection (ATCC), and the HEL1 cell line was purchased from the China Infrastructure of Cell Line Resources (catalog number KCB 86024).”
MethodInfluentialSASP: Tumor Suppressor or Promoter? Yes!
Rao, S. G., & Jackson, J. G. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2016.10.001 · Cited by 206 · see citing works
A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
Wakita, M., Takahashi, A., Sano, O., Loo, T. M., Imai, Y., Narukawa, M., Iwata, H., Matsudaira, T., Kawamoto, S., Ohtani, N., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15719-6 · Cited by 206 · see citing works
Strategies targeting cellular senescence
Ovadya, Y., & Krizhanovsky, V. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95149 · Cited by 200 · see citing works
“The solution to this problem might come from new studies on epigenetic regulators, including mixed-lineage leukemia protein 1 (MLL1), bromodomain-containing protein 4 (BRD4), and high-mobility group box 2 (HMGB2), which are responsible for reshaping the epigenetic landscape of senescent cells in a manner that would di…”
BackgroundRoles of extracellular vesicles in the aging microenvironment and age‐related diseases
Yin, Y., Chen, H., Wang, Y., Zhang, L., & Wang, X. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12154 · Cited by 199 · see citing works
Oncogene-induced senescence: a double edged sword in cancer
Liu, X., Ding, J., & Meng, L. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.198 · Cited by 191 · see citing works
The Signaling of Cellular Senescence in Diabetic Nephropathy
Xiong, Y., & Zhou, L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7495629 · Cited by 185 · see citing works
“In histones, BRD4 binds to acetylated lysines, which results in the opening of chromatin and the activation of SASP process [217].”
BackgroundLiu, P., Li, F., Lin, J., Fukumoto, T., Nacarelli, T., Hao, X., Kossenkov, A. V., Simon, M. C., & Zhang, R. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00656-3 · Cited by 180 · see citing works
Senescence as a therapeutic target in cancer and age-related diseases
McHugh, D., Durán, I., & Gil, J. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01074-4 · Cited by 199 · see citing works
“SASP expression is regulated by the mTOR pathway and involves the activation of multiple pathways including DDR 151 or p38 MAPK 152 , eventually engaging a programme involving super-enhancer remodelling 153 and activation of transcription factors such as NF-κB or C/EBPβ 154,155 .”
Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds
Wilkinson, H. N., & Hardman, M. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00773 · Cited by 173 · see citing works
Spatial and Temporal Control of Senescence
Ito, Y., Hoare, M., & Narita, M. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.07.004 · Cited by 178 · see citing works
Targeting Cancer Cells with BET Bromodomain InhibitorsPreprint
Xu, Y., & Vakoc, C. R. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026674 · Cited by 183 · see citing works
“The latter phenotype may reflect the emerging role for BRD4 in tumor suppression, and hence BET inhibition might be expected to worsen certain malignancies (Alsarraj and Hunter 2012; Fernandez et al. 2014; Tasdemir et al. 2016).”
BackgroundSelf-citationCellular senescence and the tumour microenvironment
Takasugi, M., Yoshida, Y., & Ohtani, N. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13268 · Cited by 178 · see citing works
Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies
Lucas, V., Cavadas, C., & Aveleira, C. A. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000622 · Cited by 169 · see citing works
Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence
Sen, P., Lan, Y., Li, C. Y., Sidoli, S., Donahue, G., Dou, Z., Frederick, B., Chen, Q., Luense, L. J., Garcia, B. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.01.021 · Cited by 164 · see citing works
“0001 (Figure S4C-D and TS7) based on stringent criteria reported previously(Tasdemir et al., 2016).”
BackgroundResultInfluentialThe Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging
Ghosh, K., & Capell, B. C. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.06.621 · Cited by 165 · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript epigenetic activity, inhibition of Brd4 with small molecule BET inhibitors could prevent the SASP in these studies (Tasdemir et al., 2016).”
BackgroundMuñoz, D. P., Yannone, S. M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A. M., Rodier, F., Wu, J. D., Desprez, P.-Y., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.124716 · Cited by 162 · see citing works
“So, therapeutic manipulations dampening the SASP, such as inhibitors of BET motifs (9), NF-κB (78), mTOR (79), or cGAS/STING signaling (80), may mitigate the detrimental effects of residual SnCs and restore tumor immunosurveillance.”
The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype
Hari, P., Millar, F. R., Tarrats, N., Birch, J., Quintanilla, A., Rink, C. J., Fernández-Duran, I., Muir, M., Finch, A. J., Brunton, V. G., et al. (2019) · Science Advances · doi:10.1126/sciadv.aaw0254 · Cited by 154 · see citing works
COVID-19 and cellular senescence
Schmitt, C. A., Tchkonia, T., Niedernhofer, L. J., Robbins, P. D., Kirkland, J. L., & Lee, S. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-022-00785-2 · Cited by 153 · see citing works
Watt, A. C. S., & Goel, S. (2022) · Breast Cancer Research · doi:10.1186/s13058-022-01510-6 · Cited by 151 · see citing works
Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators
Tao, W., Yu, Z., & Han, J.-D. J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.009 · Cited by 147 · see citing works
Kaempferol: Paving the path for advanced treatments in aging-related diseases
Hussain, M. S., Altamimi, A. S. A., Afzal, M., Almalki, W. H., Kazmi, I. A., Alzarea, S. I., Gupta, G., Shahwan, M. J., Kukreti, N., Wong, L. S., et al. (2024) · Experimental Gerontology · doi:10.1016/j.exger.2024.112389 · Cited by 145 · see citing works
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“BRD4, a member of Bromodomain and extraterminal domain (BET) proteins, plays pivotal roles in inflammation through assembly of acetylated histone and acetylation-dependent chromatin complexes on inflammatory genes [20, 21].”
BackgroundSenescence and the tumor-immune landscape: Implications for cancer immunotherapy
Chibaya, L., Snyder, J. T., & Ruscetti, M. A. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.02.005 · Cited by 138 · see citing works
INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors
Dietrich, C. A., Trub, A. G., Ahn, A., Taylor, M., Ambani, K., Chan, K. T., Lu, K., Mahendra, C. A., Blyth, C., Coulson, R. S., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0954 · Cited by 141 · see citing works
“Given the critical role of chromatin remodeling in governing the senescence phenotype (29, 30, 37), we performed the Assay for Transposase-Accessible Chromatin with Sequencing (ATAC-seq) on (i) parental cells treated with control vehicle or abemaciclib; (ii) abemaciclib-and abemaciclib/…”
The Chromatin Landscape of Cellular Senescence
Criscione, S. W., Teo, Y. V., & Neretti, N. (2016) · Trends in Genetics · doi:10.1016/j.tig.2016.09.005 · Cited by 137 · see citing works
“For example, it was recently reported that in OIS, the enhancer landscape undergoes global remodeling, with recruitment of BRD4 to newly activated super-enhancers proximal to SASP genes [91].”
BackgroundCancer and Aging - the Inflammatory Connection
Zinger, A., Cho, W. C. S., & Ben‐Yehuda, A. (2017) · Aging and Disease · doi:10.14336/ad.2016.1230 · Cited by 137 · see citing works
“ChIP-seq analysis showed that BRD4 is recruited to the new SE and participate in regulation of critical SASP genes [72].”
MethodLi, D., Wang, J., Zhang, M., Hu, X., She, J., Qiu, X., Zhang, X., Xu, L., Liu, Y., & Qin, S. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.11.003 · Cited by 136 · see citing works
“Mountains of evidence showed that histone modifications were one of the manners to regulate gene expression.22 Among diverse kinds of the histone modifications, H3K27ac mark was especially recognized by the BET family of bromodomain proteins, such as BRD4.”
BackgroundSARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress
Chang, R. P., Mamun, A., Dominic, A., & Le, N. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.605908 · Cited by 131 · see citing works
Putting the brakes on the cell cycle: mechanisms of cellular growth arrest
Pack, L. R., Daigh, L. H., & Meyer, T. (2019) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.05.005 · Cited by 130 · see citing works
“Alterations in chromatin dynamics may contribute to increased transcription of inflammatory cytokines in senescent cells [67,68].”
BackgroundEpigenetic Regulation of Cellular Senescence
Crouch, J. D., Shvedova, M., Thanapaul, R. J. R. S., Botchkarev, V. A., & Roh, D. S. (2022) · Cells · doi:10.3390/cells11040672 · Cited by 132 · see citing works
“Further, pharmacological inhibition of BRD4 allowed for immune escape and decreased clearance of premalignant senescent hepatocytes in a liver cancer mouse model [121].”
BackgroundInfluentialTargeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
Song, S., Tchkonia, T., Jiang, J., Kirkland, J. L., & Sun, Y. (2020) · Advanced Science · doi:10.1002/advs.202002611 · Cited by 129 · see citing works
YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6
Chen, S., Lǚ, K., Hou, Y., You, Z., Shu, C., Wei, X., Wu, T., Shi, N., Zhang, G., Wu, J., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006020 · Cited by 129 · see citing works
Chibaya, L., Murphy, K. C., DeMarco, K. D., Gopalan, S., Liu, H., Parikh, C. N., Lopez-Diaz, Y., Faulkner, M., Li, J., Morris, J. P., et al. (2023) · Nature Cancer · doi:10.1038/s43018-023-00553-8 · Cited by 131 · see citing works
Self-citationEmerging roles of and therapeutic strategies targeting BRD4 in cancer
White, M. E., Fenger, J. M., & Carson, W. E. (2019) · Cellular Immunology · doi:10.1016/j.cellimm.2019.02.001 · Cited by 124 · see citing works
“Senescent cells normally maintain a closed chromatin configuration; however, cancer cells can acquire a secretory-associated senescent phenotype (SASP) whereby oncogene-induced senescence results in remodeling of the enhancer landscape and recruitment of BRD4 [21].”
BackgroundInfluentialKang, C. (2019) · Europe PMC (PubMed Central) · doi:10.14348/molcells.2019.0298 · Cited by 125 · see citing works
“, 2015); BRD4 functions as an epigenetic reader to modulate lineage- and cellular state-specific transcription (Tasdemir et al., 2016); finally, cGAS-STING is a component of the innate immune system that senses the presence of cytosolic DNA (Yang et al.”
BackgroundInfluentialCellular senescence in lung cancer: Molecular mechanisms and therapeutic interventions
Jha, S. K., Rubis, G. D., Devkota, S. R., Zhang, Y., Adhikari, R., Jha, L. A., Bhattacharya, K., Mehndiratta, S., Gupta, G., Singh, S. K., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102315 · Cited by 122 · see citing works
“When HRAS G12V -induced senescent human cultured fibroblasts were injected into mice, it was observed that the super-enhancer landscape in these cells underwent global remodeling (Regis et al., 2009; Tasdemir et al., 2016) .”
Bromodomain 4: a cellular Swiss army knife
Devaiah, B. N., Gégonne, A., & Singer, D. S. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.2ri0616-250r · Cited by 120 · see citing works
“senescence, although it is not clear what determines which will occur [47] (unpublished observations).”
BackgroundCellular senescence: Neither irreversible nor reversible
Reimann, M., Lee, S., & Schmitt, C. A. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20232136 · Cited by 120 · see citing works
A common signature of cellular senescence; does it exist?
Sikora, E., Bielak-Żmijewska, A., & Mosieniak, G. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101458 · Cited by 120 · see citing works
The Paradoxical Role of Cellular Senescence in Cancer
Yang, J., Liu, M., Hong, D., Zeng, M., & Zhang, X. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.722205 · Cited by 115 · see citing works
“Furthermore, IL-6 may cooperate with HER2 in the process of tumor development (Korkaya et al., 2012; Tivari et al., 2018).”
BackgroundThe role of epigenetics in renal ageing
Shiels, P. G., McGuinness, D., Eriksson, M., Kooman, J. P., & Stenvinkel, P. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.78 · Cited by 114 · see citing works
Oncogene-induced senescence: From biology to therapy
Zhu, H., Blake, S., Kusuma, F. K., Pearson, R. B., Kang, J., & Chan, K. T. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111229 · Cited by 116 · see citing works
The Functions of BET Proteins in Gene Transcription of Biology and Diseases
Cheung, K. L., Kim, C., & Zhou, M. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.728777 · Cited by 111 · see citing works
“…studies to identify key genes and reveal mechanisms of BET proteins in disease-related cell types and genes such as rheumatoid arthritis synovial fibroblasts (Krishna et al., 2021), ESC pluripotency genes (Di Micco et al., 2014), and senescence-associated secretory genes (Tasdemir et al., 2016).”
BackgroundWatt, A. C., Cejas, P., DeCristo, M. J., Metzger-Filho, O., Lam, E., Qiu, X., BrinJones, H., Kesten, N., Coulson, R., Font-Tello, A., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-00135-y · Cited by 94 · see citing works
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Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging
Sun, Y., Li, Q., & Kirkland, J. L. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac030 · Cited by 105 · see citing works
- Authors
- Tasdemir, N., Banito, A., Roe, J.-S., Alonso-Curbelo, D., Camiolo, M., Tschaharganeh, D. F., Huang, C.-H., Aksoy, O., Bolden, J. E., Chen, C.-C., Fennell, M., Thapar, V., Chicas, A., Vakoc, C. R., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cold Spring Harbor Laboratory (US)
- 1Memorial Sloan Kettering Cancer Center, New York, New York.
- Stony Brook University (US)
- Corresponding author
- Vakoc, Christopher R.
- Lowe, Scott W.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2016-06-01
- Volume
- 6
- Issue
- 6
- Pages
- 612-629
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4893996
- OpenAlex
- W2342055991
- Cited by
- 415
- References
- 78
- Citations by year
- 2026: 42 · 2025: 41 · 2024: 62 · 2023: 44 · 2022: 51 · 2021: 49 · 2020: 36 · 2019: 34 · 2018: 20 · 2017: 28 · 2016: 8
- FWCI
- 24.15
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- Funders
- National Institutes of Health (1s10od020122-01, 5p30ca045508-35)
- National Institute on Aging (R56AG016379, R01AG016379)
- National Cancer Institute (P30-CA045508, R01CA174793, P01CA013106, P30CA008748)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- BRD4, super-enhancers, enhancer remodeling, oncogene-induced senescence, senescence-associated secretory phenotype, chromatin reader proteins, paracrine signaling, tumor suppression, senescent cell elimination
- MeSH terms
- Bromodomain Containing Proteins, Animals, Binding Sites, Cell Cycle, Enhancer Elements, Genetic, Fibroblasts, Gene Expression Regulation, Histones, Humans, Immunologic Surveillance, Membrane Proteins, Nuclear Proteins, Oncogenes, Protein Binding, Transcription Factors, Cluster Analysis, Cellular Senescence, Cell Cycle Proteins, Computational Biology, Paracrine Communication, GTP Phosphohydrolases, Gene Expression Profiling, Hepatocytes, Chromatin Assembly and Disassembly, Cell Line, Tumor, Chromatin Immunoprecipitation, Cell Proliferation, Mice, Position-Specific Scoring Matrices, High-Throughput Nucleotide Sequencing, Nucleotide Motifs
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