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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 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]
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“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]
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“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]
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“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]
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In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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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Citations
Cites
The serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508 · cited 1×
“Although initially defined as a phenotype of cultured fibroblasts (3), cellular senescence appears to have a broad impact on human health and disease.”
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218
Self-citationThe senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · cited 1×
“Conversely, senescent cells activate the expression of genes known to influence the tissue microenvironment, including matrix remodeling enzymes, growth factors, and immunemodulatory cytokines (22, 23).”
GREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502 · cited 1×
“The Genomic Regions Enrichment of Annotations Tool (GREAT) was used to predict GO terms of ChIP-Seq–enriched regions (77).”
Histone H3K27ac separates active from poised enhancers and predicts developmental state
Creyghton, M. P., Cheng, A. W., Welstead, G. G., Kooistra, T., Carey, B. W., Steine, E. J., Hanna, J., Lodato, M. A., Frampton, G. M., Sharp, P. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016071107 · Cited by 4,302 · cited 1×
“Following lysis of cross-linked proliferating, senescent, and quiescent IMR90 cells, the enhancer landscape was visualized using chromatin immunoprecipitation coupled with highthroughput sequencing (ChIP-Seq) using the histone modification H3K27Ac as a marker of active enhancers (45).”
MethodSelective inhibition of BET bromodomains
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., et al. (2010) · Nature · doi:10.1038/nature09504 · Cited by 4,262
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143 · cited 4×
“For example, in embryonic stem cells (ESC), exceptionally large stretches of H3K27Ac-marked regulatory elements, termed super-enhancers (SE), are associated with genes that play prominent roles in ESC self-renewal (37, 38).”
InfluentialSuper-enhancers in the control of cell identity and disease
Hnisz, D., Abraham, B. J., Lee, T. I., Lau, A., Saint-André, V., Sigova, A. A., Hoke, H. A., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.09.053 · Cited by 3,662 · cited 4×
“For example, in embryonic stem cells (ESC), exceptionally large stretches of H3K27Ac-marked regulatory elements, termed super-enhancers (SE), are associated with genes that play prominent roles in ESC self-renewal (37, 38).”
InfluentialSelective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961 · cited 8×
“BRD4 Is Recruited to Senescence-Activated SEs Associated with Key SASP Genes One of the proteins that bind acetylated histones at enhancers and are enriched in SEs is the transcriptional coactivator BRD4, which couples enhancer remodeling to RNA Pol II elongation (39).”
InfluentialSelf-citationBET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Delmore, J. E., Issa, G. C., Lemieux, M. E., Rahl, P. B., Shi, J., Jacobs, H. M., Kastritis, E., Gilpatrick, T., Paranal, R. M., Qi, J., et al. (2011) · Cell · doi:10.1016/j.cell.2011.08.017 · Cited by 2,888 · cited 1×
“Our data linking BRD4 to a tumor-suppressive program stands in apparent contrast to the established role of BRD4 in tumors as a cancer maintenance gene (39, 53, 68).”
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Items 301–400 of 415
Manji, J., Pipella, J., Brawerman, G., & Thompson, P. J. (2024) · Epigenomes · doi:10.3390/epigenomes8010010 · Cited by 4
“The Ino80 complex is a highly conserved ATP-dependent chromatin remodeling complex, involved in transcription, replication, and DNA repair [22] while Ino80 contributes to activation of super-enhancers in the context of cancer [25], a feature shared with Brd4 in the context of senescence [13].”
BackgroundPharmacological potential of cyclic nucleotide signaling in immunity
Ednacot, E. M. Q., Nabhani, A., Dinh, D. M., & Morehouse, B. R. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108653 · Cited by 5
Functional screening to identify senescence regulators in cancer
Lujambio, A., & Banito, A. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.02.001 · Cited by 6
Self-citationTPR is required for cytoplasmic chromatin fragment formation during senescence
Bartlett, B. M., Kumar, Y., Boyle, S., Chowdhury, T., Quintanilla, A., Boumendil, C., Acosta, J. C., & Bickmore, W. A. (2024) · eLife · doi:10.7554/elife.101702 · Cited by 4
A novel combination treatment against melanoma with NRAS mutation and therapy resistance
Yu, Y. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201708573 · Cited by 5
Olp, M. D., Jackson, V. E., & Smith, B. C. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/699967 · Cited by 5
“Brd4 ChIP-Seq datasets from HUVEC (GSM1305201) (49), K562 (ENCFF260JHC) and IMR90 (GSM1915116) (95) cells were converted from Bedgraph and Wig to BigWig format when necessary using the UCSC Genome Browser applications bedGraphToBigWig and wigToBigWig, respectively.”
MethodImpact of Aging and Cellular Senescence in the Pathophysiology of Preeclampsia
Suvakov, S. R., Kattah, A. G., Gojković, T., Enninga, E. A. L., Pruett, J. E., Jayachandran, M., Sousa, C., Santos, J., Hassan, C. A., Suarez, M. L. G., et al. (2023) · Comprehensive physiology · doi:10.1002/cphy.c230003 · Cited by 6
“It is important to emphasize that the SASP secretome not only has deleterious effects by spreading senescence, but is also important in initiating tissue repair and promoting the immune clearance of injured cells (486, 520).”
Mosaic Regulation of Stress Pathways Underlies Senescent Cell HeterogeneityPreprint
Avelar, R. A., Duffield, T., Lagger, C., Krstevska, N., Breuer, M., & de Magalhães, J. P. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.03.616489 · Cited by 5
“Knockdown of BRD4 blunts SASP gene expression in OIS and SIPS even after cells have established a senescence phenotype [26].”
BackgroundWang, R., Li, A., & Pang, Z. (2025) · Frontiers in Genetics · doi:10.3389/fgene.2025.1611905 · Cited by 7
de Mendonça, L. B., Lenz, G., & Filippi‐Chiela, E. C. (2025) · Biochemical Society Transactions · doi:10.1042/bst20253054 · Cited by 5
“Inhibition of BRD4 disrupts SASP-driven paracrine effects, compromises immune surveillance, and reduces macrophage polarization and NK cells’ activity, underscoring its role in determining SenStates [122].”
Space radiation induces distinct senescent phenotypes: Implications for space travel
Pitcher, L. E., Mukherjee, B., Saathoff, A. M., Eduvas, Z. A., Bartz, J., Zhang, X., Giorgadze, N., Pirtskhalava, T., Habib, A. A., LeBrasseur, N. K., et al. (2025) · npj Aging · doi:10.1038/s41514-025-00272-7 · Cited by 5
“After irradiation, cell passaging was tracked over 14 days, which revealedthat exposure to either Fe or H irradiation had the most signi fi cant impactonpassagingratecomparedtothemockcontrol,evenat0.”
Metabolic, epigenetic, and immune crosstalk in ovarian aging
Li, J., Liao, Q., Yang, Y., Wang, K., Liu, W., Zhou, F., Liu, H., & Zhang, Y. (2026) · iScience · doi:10.1016/j.isci.2026.114733 · Cited by 7
“121 In addition, external factors such as gut microbial metabolites are also involved in this network.”
Hematopoiesis: a BETter understanding
Dasgupta, N., & Adams, P. D. (2023) · EMBO Reports · doi:10.15252/embr.202357927 · Cited by 4
“Similarly, senescent fibroblasts experience global enhancer landscape remodeling, with BRD4 recruited to newly activated SEs near key SASP genes (Tasdemir et al , 2016).”
Mechanical Rejuvenation of Mesenchymal Stem Cells from Aged PatientsPreprint
Massidda, M. W., Demkov, A., Sices, A., Lee, M., Lee, J., Paull, T. T., Kim, J., & Baker, A. B. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.06.597781 · Cited by 5
Ooki, T., Hayashi, T., Yamamoto, Y., & Hatakeyama, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.28.635202 · Cited by 4
Holloway, K., Neherin, K., Song, Y., Sato, K., Houston, A., Chen, F., Li, D., & Zhang, H. (2025) · Aging Cell · doi:10.1111/acel.14472 · Cited by 3
“…(SASP) (Casella et al. 2019; De Cecco et al. 2019; Fridman and Tainsky 2008; Hernandez-Segura et al. 2017; Jochems et al. 2021; Saul et al. 2022; Shah et al. 2013; Tasdemir et al. 2016) and found no significant enrichment of these gene signatures in pAAVS1- p16-iPSCs after Dox treatment (Table S7).”
Cellular senescence: A novel mechanism of therapeutic resistance in prostate cancer
Lin, C., Hadfield, M. J., Rathore, A., Pinho-Schwermann, M. P., Zhang, S., Lu, S., den Hollander, P., Mani, S. A., Seyhan, A. A., Santopietro, A., et al. (2025) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2025.103061 · Cited by 4
Natural Products as Anti-Senescence-Associated Secretory Phenotype (SASP) Agents
Yang, L., Liu, Y., Li, Y., Fu, P., & Ma, L. (2026) · Current Medicinal Chemistry · doi:10.2174/0109298673399133251206205537 · Cited by 4
Advances in targeted protein degradation for cancer immunotherapy
Sun, Y., Li, M., Zou, Y., & Shi, B. (2026) · Cell Biomaterials · doi:10.1016/j.celbio.2026.100403 · Cited by 3
Investigation of the impact of bromodomain inhibition on cytoskeleton stability and contraction
Bigger-Allen, A. A., Gheinani, A. H., & Adam, R. M. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01553-6 · Cited by 3
“…with undefined growth medium (GSE138323), rat cardiac fibroblasts stimulated TGFβ (GSE127229) [30], Rheumatoid Synovial Fibroblasts stimulated with IL1B (GSE148395) [42] and IMR90 human airway fibroblasts treated without or with JQ1, or in which BRD4 was knocked down using RNAi (GSE74324) [32].”
BackgroundRole of BRD4 in cancer – A review
Samani, K., Sharma, U. R., Sharma, A. R., Pm, M., & V, S. (2020) · IP Journal of Diagnostic Pathology and Oncology · doi:10.18231/j.jdpo.2020.027 · Cited by 4
Olan, I., & Narita, M. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202106164 · Cited by 3
Wang, R., Liu, N., Li, G., Liu, J., Ma, X., Liu, X., & Li, J. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1160599 · Cited by 3
“Importantly, in colorectal cancer, PRR7-AS1 expression was positively correlated with the expression of BRD4, the primary H3K27ac signal reader (Tasdemir et al., 2016) (Figure 10C).”
BackgroundMultivalent nucleosome scaffolding by bromodomain and extraterminal domain tandem bromodomains
Olp, M. D., Bursch, K. L., Wynia‐Smith, S. L., Nuñez, R., Goetz, C. J., Jackson, V. E., & Smith, B. C. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108289 · Cited by 3
Picallos-Rabina, P., Silva‐Álvarez, S. D., Antelo-Iglesias, L., Triana-Martínez, F., & Collado, M. (2020) · Healthy ageing and longevity · doi:10.1007/978-3-030-44903-2_5 · Cited by 3
Hu, J., Yu, D., Wu, D., Wang, J., Cai, Y., Du, X., Ji, J., & Ouyang, H. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.15.537012 · Cited by 3
Acetylation of histone H2B on lysine 120 regulates BRD4 binding to intergenic enhancersPreprint
Hamilton, G. A., Ruiz, P. D., Ye, K. Q., & Gamble, M. J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.07.637147 · Cited by 3
The Emerging Role of Senolysis in Atherosclerosis
Vagena, S., Theocharous, G., Theodorou, A., Pantelis, P., Gravanis, M., Tscheuschner, L., Theodorou, A., Galyfos, G. C., Sigala, F., Lаgopati, N., et al. (2025) · Medicina · doi:10.3390/medicina61122137 · Cited by 3
“The accomplishment of prolonged cytokine production from the macrophages requires several mechanisms, such as the elevated presence of super-enhancers associated with inflammatory responses (e.g., H3K27ac-rich loci) and NF-κ B co-activation [58].”
Wang, X., Feng, Z., Sun, S., Zhang, J., Wang, K., Wang, Y., Zhao, Y., Zhao, B., Liu, B., Sun, M., et al. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102983 · Cited by 2
Etoh, K., Hino, Y., Morishita, H., & Nakao, M. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.03.020 · Cited by 2
Molecular mechanisms and recent advances in cellular senescence
Hussain, A., Tatar, M., & Gong, R. (2026) · Cell & Bioscience · doi:10.1186/s13578-026-01596-x · Cited by 2
“Studies with fibroblasts and human melanocytes confirm that, H3K4 methyl transferase (MLL1) is important for SASP development, as silencing of the same with RNA interference results in reduced expression of SASP components [429].”
Wei, R., Liu, D., Shu, K., & Zhu, H. (2026) · Drug Resistance Updates · doi:10.1016/j.drup.2026.101444 · Cited by 2
Immune surveillance and immune evasion of senescent cells
Garcia-Baucells, P., Serrano, M., & Amor, C. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01335-w · Cited by 4
Epiregulation of the SASP makes good neighbors
Desbats, M. A., Zumerle, S., & Alimonti, A. (2021) · Nature Aging · doi:10.1038/s43587-021-00068-w · Cited by 2
Spurious transcription may be a hallmark of aging
Isima, N., & Gil, J. (2023) · Nature Aging · doi:10.1038/s43587-023-00398-x · Cited by 2
Current Methodologies to Assess Cellular Senescence in Cancer
Laouris, P., & Muñoz‐Espín, D. (2025) · Methods in molecular biology · doi:10.1007/978-1-0716-4426-3_2 · Cited by 2
Liu, Y., Zheng, Z., Fang, W., Li, Y.-S., Li, Q., Yang, M., Han, D.-C., Zhou, J., Xie, Y.-H., Zhang, Y., et al. (2025) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2025.03.001 · Cited by 2
Comparative analysis of gene regulation in single cells using Compass
Wan, C., Qu, Y., Ye, Z., Zhang, T., Ma, H.-F., Chen, M., Hou, W., & Ji, Z. (2025) · Cell Reports Methods · doi:10.1016/j.crmeth.2025.101035 · Cited by 2
Keen, J. L., Al‐Naamani, N., & Ventetuolo, C. E. (2023) · Advances in Pulmonary Hypertension · doi:10.21693/1933-088x-22.1.55 · Cited by 2
Martínez‐Zamudio, R. I., & Herbig, U. (2019) · Springer eBooks · doi:10.1007/978-3-319-69892-2_38-1 · Cited by 2
Moore, M., Pardo, L., Mitchell, L. E., Schmidt, T., Waldron, J. A., May, S., Müller, M., Smith, R. C. L., Strathdee, D., Bryson, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.16.553544 · Cited by 2
“A major challenge to the cell is posed by the hugely increased flux of soluble and integral membrane proteins through the ER and Golgi which accompany acquisition of the SASP.”
BackgroundInfluentialNadeem, J., Parveen, A., & Kim, S. Y. (2023) · Preprints.org · doi:10.20944/preprints202309.1932.v1 · Cited by 1
Inflammatory β-Cell Stress and Immune Surveillance in Type 1 DiabetesPreprint
Bhushan, A., & Thompson, P. J. (2024) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041605 · Cited by 4
Kim, H., Kummerfeld, E., Niedernhofer, L. J., Aliferis, C., Robbins, P. D., & Wang, J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27073012 · Cited by 1
“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].”
Martins-Silva, R., Kaizeler, A., & Barbosa‐Morais, N. L. (2026) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqag057 · Cited by 1
Altulea, A., Mackedenski, S. J., Nehme, J., & Demaria, M. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00845-6 · Cited by 1
“To represent cell cycle activation in the context of cellular senescence, we included senescent cells with p53, p16, or p21 knockdown (Tasdemir et al, 2016).”
Epigenetic regulation in osteoarthritis: recent updates and emerging mechanisms
Zhao, Y., & Liu, X. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1862466 · Cited by 2
“Conversely, reduced super-enhancer activity at key regulatory regions required for maintaining the normal chondrocyte phenotype may contribute to the loss of cartilage-protective functions (Tasdemir et al., 2016).”
Xu, Z., Guo, J., Liu, Z., Yu, J., Yuan, R., Min, Y., Wei, Z., & Peng, X. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103270 · Cited by 1
Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer
Hinterleitner, C., Barthet, V. J. A., Goldberg, H. V., Vogt, K. C., Perea, A. M., Hillger, L. R., Ruiz, S. B., McHugh, D., Ho, Y.-J., Perez, A. C., et al. (2026) · Science · doi:10.1126/science.aeg4791 · Cited by 1
“The second SMNP type encapsulated the senomorphic agent dBET6, a proteolysis-targeting chimera (PROTAC) degrading bromodomain-containing protein 4 (BRD4) that disrupts enhancer function and suppresses expression of senescence-associated secretory phenotype (SASP) genes (60), generating FidBET6 (47).”
Self-citationPotential Applications of Aptamers for Targeting Senescent Cells
Leonardi, A., Pacifico, F., & Crescenzi, E. (2020) · Healthy ageing and longevity · doi:10.1007/978-3-030-44903-2_10 · Cited by 1
Thompson, P. J., & Bhushan, A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822514-1.00008-0 · Cited by 1
Palminha, N. M., Hashish, S. A., Rabie, E., & Saber, S. (2022) · Nutritional neurosciences · doi:10.1007/978-981-16-9205-5_4 · Cited by 1
Giorgio, E. D., Paluvai, H., Dalla, E., Ranzino, L., Renzini, A., Moresi, V., Cutano, V., Picco, R., & Brancolini, C. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.04.132787 · Cited by 2
“Other oncogenes of viral origin, like E1A and its ΔC-fragment (1-143), are able to overcome OIS, by targeting p16/Rb pathways22.”
BackgroundMeyer, K., Patra, T., Mahantesh, V., & RAY, R. K. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.16.440215 · Cited by 1
“Brd4 has been observed to be required in senescence immune surveillance and SASP associated paracrine signaling (17).”
BackgroundReen, V., & Gil, J. (2021) · Science · doi:10.1126/science.abm3229 · Cited by 1
Mourragui, S. M. C., Siefert, J. C., Reinders, M. J. T., Loog, M., & Wessels, L. F. A. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.08.483431 · Cited by 1
“Both cell lines show enrichment for genes involved in senescence, reminiscent of the effects of BRD4 inhibition 53,54 .”
BackgroundSystematic transcriptomic analysis and temporal modelling of the senescent human fibroblastPreprint
Scanlan, R.-L., Pease, L., O’Keefe, H., Guimera, A. M., Shanley, D., & Wordsworth, J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.16.504144 · Cited by 1
An integrated RNA-proteomic landscape of drug induced senescence in a cancer cell linePreprint
Stevenson, T., Al-Roshdi, M., Görtler, F., & Grellscheid, S. N. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.03.21.533605 · Cited by 1
“The SASP is thought to have evolved to aid in eliminating senescent/neoplastic populations through the recruitment of immune cells [3, 12].”
BackgroundMartínez‐Zamudio, R. I., & Herbig, U. (2021) · Springer eBooks · doi:10.1007/978-3-030-22009-9_38
Faculty Opinions recommendation of Senolytic CAR T cells reverse senescence-associated pathologies.
Pawelec, G. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.738152729.793576459
Han, J. J. (2017) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.731684713.793537520
Avvedimento, E. (2017) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.731684713.793538341
Küçükgüven, A., & Vargel, İ. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-98804-9.00032-3
Aging principles and interventional perspectives
Sikora, E. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90581-7.00002-5
A cFLIP-flop switch for senolysis
Fan, D. N.-Y., & Schmitt, C. A. (2022) · Nature Cancer · doi:10.1038/s43018-022-00455-1
Shigeta, S., Lui, G. Y. L., Shaw, R. C., Moser, R. D., Gurley, K. E., Durenberger, G., Rosati, R., Diaz, R. L., Ince, T. A., Swisher, E. M., et al. (2023) · doi:10.1158/1535-7163.c.6543286.v1
Shigeta, S., Lui, G. Y. L., Shaw, R. C., Moser, R. D., Gurley, K. E., Durenberger, G., Rosati, R., Diaz, R. L., Ince, T. A., Swisher, E. M., et al. (2023) · doi:10.1158/1535-7163.c.6543286
Data from Senescence 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. (2023) · doi:10.1158/2159-8290.c.6549996.v1
Self-citation(2023) · Advances in Pulmonary Hypertension · doi:10.21693/1933-0898-22.1.i
Senescent Subtypes Transition ModelPreprint
Singh, G. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.10.544466
“SASP induction involves recruitment of BRD4 to senescence-activated super-enhancers adjacent to SASP factor genes [17].”
BackgroundAn integrated RNA-proteomic landscape of drug induced senescence in a cancer cell line
Stevenson, T., Al-Roshdi, M., Görtler, F., & Grellscheid, S. N. (2023) · F1000Research · doi:10.12688/f1000research.133203.1
Norman, J. C., Moore, M. H., Pardo, L., Mitchell, L. E., Schmidt, T., Waldron, J. A., May, S., Müller, M., Smith, R. C. L., Strathdee, D., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-3891270/v1
¿Combatir la senescencia para un envejecimiento saludable?
Resano, M. M. (2024) · doi:10.18567/sebbmdiv_r.202403
Pardo, L., Moore, M., Deshmukh, R. S., Powley, I. R., Waldron, J. A., Kruspig, B., McGarry, L., Wood, C. S., Leslie, H., Hughes, M. M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.19.644135
“…thought that if activated oncogenes can evoke sufficient senescent hallmarks to slow growth and produce SASP to attract immune cells, thus providing opportunities for clearance of mutated cells, adoption of senescence hallmarks may constitute an important tumour-suppression mechanism [19, 20, 36].”
Li, G., Ma, L., Feng, C., Yin, H., Bao, J., Wu, D., Zhang, Z., Li, X., Li, Z., Yang, C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25237385
Redmer, T., Raigel, M., Sternberg, C., Ziegler, R., Probst, C., Lindner, D., Aufinger, A., Limberger, T., Trachtová, K., Kodajova, P., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26727013
Redmer, T., Raigel, M., Sternberg, C., Ziegler, R., Probst, C., Lindner, D., Aufinger, A., Limberger, T., Trachtová, K., Kodajova, P., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26727004
Redmer, T., Raigel, M., Sternberg, C., Ziegler, R., Probst, C., Lindner, D., Aufinger, A., Limberger, T., Trachtová, K., Kodajova, P., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26727010
Giorgio, E. D., Paluvai, H., Dalla, E., Ranzino, L., Renzini, A., Moresi, V., Minisini, M., Picco, R., & Brancolini, C. (2021) · Figshare · doi:10.6084/m9.figshare.14562731
Giorgio, E. D., Paluvai, H., Dalla, E., Ranzino, L., Renzini, A., Moresi, V., Minisini, M., Picco, R., & Brancolini, C. (2021) · Figshare · doi:10.6084/m9.figshare.14562755
Redmer, T., Raigel, M., Sternberg, C., Ziegler, R., Probst, C., Lindner, D., Aufinger, A., Limberger, T., Trachtová, K., Kodajova, P., et al. (2024) · MDC Repository (Max-Delbrueck-Center for Molecular Medicine) · doi:10.6084/m9.figshare.26727007
Sun, W., Hu, Y., Lan, T., Ma, Y., Wu, Y., Pan, C., Mai, L., & Lin, Z. (2026) · Discover Oncology · doi:10.1007/s12672-026-04471-w
Plasminogen Activator Inhibitor 1, Cell Senescence, and Aging-Related Diseases
Liu, R.-M., & Nakamya, M. F. (2026) · Cells · doi:10.3390/cells15060551 · Cited by 1
“SASP arises from persistent DDR signaling via ATM-CHK2-p53 and is transcriptionally governed by NF-κ B and C/EBP β , with additional modulation through cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathways [18,86–91].”
Kuklinkova, R., Benova, N., Kohli, J. S., Boyne, J. R., Roberts, W., & Anene, C. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.20.713302
de Jong, D. (2018) · theses.fr (ABES) · doi:10.70675/27595e3bzbf8ez4196zb9b4z036b359e6b5c
Zhang, X., Yang, L., He, X., Zhao, M., Fang, Z., Xu, G., Duan, Z., & Luo, K. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.03.050
“Although positive and negative effects of senescence have been identified and reviewed in this article, the dual role of the SASP is insufficiently, non-systematically considered for Nano-DDSs design 235 .”
de Freitas, J. A. N. L. F. (2020) · theses.fr (ABES) · doi:10.70675/0e6e3614z3915z4fb8za2cdz24b40b9679b2
The role of Activin signaling pathway in the initiation and progression of pancreatic cancer
Zhao, Y. (2019) · theses.fr (ABES) · doi:10.70675/17612dbdz6d94z4563z86a3z6d1e91b34f9b
Plasticité cellulaire et initiation tumorale dans le modèle du cancer du sein
Blander, H. D. (2020) · theses.fr (ABES) · doi:10.70675/c6b4eda8z19a5z4b3dzb7d9zacc5fd814b21
Reyes, J. (2026) · Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) · doi:10.5281/zenodo.18892592
Clofoctol as a novel senolytic drug eliminating therapy-induced senescent glioma cells
Zhang, Y. Y., Wang, Z., Wang, Y., Li, E., Wu, F., Hou, L., Yin, B., Qiang, B., Han, W., & Peng, X. (2026) · Neuro-Oncology Advances · doi:10.1093/noajnl/vdag102
Cell-autonomous immunity model of aging and disease
Wu, F., Winer, D. A., & Furman, D. (2026) · Trends Open · doi:10.1016/j.treopn.2026.04.012
Cellular senescence in Crohn’s disease: a double-edged sword in intestinal fibrosis
Liu, J., & Yu, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1825690
“Epigenetic modi fi ers, such as the BRD4 inhibitor IBET762 (233) and the histone deacetylase (HDAC) inhibitor Trichostatin A (234), also effectively suppress SASP expression.”
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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