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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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Wang, X., Zhou, Y., Peng, Y., Huang, T., Xia, F., Yang, T., Duan, Q., & Zhang, W. (2019) · Experimental Cell Research · doi:10.1016/j.yexcr.2019.111507 · Cited by 25
Yang, L. C., You, J., Yang, X., Jiao, R., Xu, J., Zhang, Y., Mi, W., Zhu, L., Ye, Y., Ren, R., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57334-3 · Cited by 28
“Histone acetylation on SASP gene super-enhancers and enhancers featured by lysine 27 acetylated histone H3 (H3K27ac), and the interaction with transcription factor NF κ B, play pivotal roles in the activation of SASP gene transcription 45,46 .”
Senescence: An Identity Crisis Originating from Deep Within the Nucleus
Olan, I., & Narita, M. (2022) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-120420-013537 · Cited by 25
WSTF nuclear autophagy regulates chronic but not acute inflammation
Wang, Y., Eapen, V. V., Liang, Y., Kournoutis, A., Sherman, M. S., Xu, Y., Onorati, A., Li, X., Zhou, X., Corey, K. E., et al. (2025) · Nature · doi:10.1038/s41586-025-09234-1 · Cited by 30
Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype
Joung, J., Heo, Y., Kim, Y., Kim, J., Choi, H., Jeon, T., Jang, Y., Kim, E.-J., Lee, S. H., Suh, J. M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56929-0 · Cited by 26
Leal, A. S., Liu, P., Krieger-Burke, T., Ruggeri, B., & Liby, K. T. (2020) · Cancers · doi:10.3390/cancers13010096 · Cited by 23
COSTA, A. V., Facchini, G., Pinheiro, A. L. T. A., da Silva, M. S., Bonner, M. Y., Arbiser, J. L., & Eberlin, S. (2017) · International Journal of Dermatology · doi:10.1111/ijd.13569 · Cited by 24
Hoare, M., & Narita, M. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-89512-3_15 · Cited by 23
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Zhang, B., Lam, E. W. ‐., & Sun, Y. (2018) · Aging Cell · doi:10.1111/acel.12875 · Cited by 24
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Zhang, X., Wang, Y., Chiang, H.-C., Hsieh, Y.-P., Lu, C., Park, B. H., Jatoi, I., Jin, V. X., Hu, Y., & Li, R. (2019) · Breast Cancer Research · doi:10.1186/s13058-019-1132-1 · Cited by 22
“Genome-wide study found that BRD4 co-localizes with H3K27ac [46, 85], and its binding with acetylated histones is important for maintenance of higher-order chromatin structure [86].”
BackgroundBalamurli, G., Liew, A. Q. X., Tee, W., & Pervaiz, S. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103441 · Cited by 23
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“In addition, when analyzing H3K27ac ChIP-Seq data from senescent IMR90 cells (Tasdemir et al, 2016; Data ref: Tasdemir et al, 2016), we observed a signi fi cant increase in the H3K27ac signal intensity — a substrate of SIRT6 — within the PAX5 promoter region (Fig.”
Wang, C., Tanizawa, H., Hill, C., Havas, A. P., Zhang, Q., Liao, L., Xue, H., Lei, X., Wang, L., Nie, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49745-5 · Cited by 23
“To unravel the regulatory mechanism by which the MTC promotes HK2 expression, we fi rst cross-referenced publicly available H3K27Ac ChIP-seq, METTL3, and METTL14 Cut&Run-seq 10,20 .”
Jiang, X., Baig, A. H., Palazzo, G., Pizzo, R. D., Borteçen, T., Groessl, S., Zaal, E. A., Ramirez, C. C. A., Kowar, A., Huerta, D. A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51901-w · Cited by 20
“To this end, weemployed a well-established in vivo model for OIS 5,45 .”
Self-citationHuff, L. A., Yan, S., & Clemens, M. G. (2021) · Antioxidants · doi:10.3390/antiox10071146 · Cited by 21
Sfera, A., Thomas, K. G., Andronescu, C. V., Jafri, N., Sfera, D. O., Sasannia, S., del Campo, C. M. Z.-M., & Maldonado, J. C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.904816 · Cited by 21
“senescence-associated secretory phenotype (SASP), a ferroptosis resistant cellular program (Tasdemir et al., 2016; Sui et al., 2019; Lam et al., 2020; Tang et al., 2022).”
BackgroundSong, S., Perez, J. V., Svitko, W., Ricketts, M. D., Dean, E., Schultz, D., Marmorstein, R., & Johnson, F. B. (2019) · Aging Cell · doi:10.1111/acel.13061 · Cited by 20
“…mammalian factors controlling gene expression changes in senescent cells, because several can be manipulated to blunt the altered expression without bringing senescent cells out of cell cycle arrest (Correia-Melo et al., 2016; Georgilis et al., 2018; Nacarelli et al., 2019; Tasdemir et al., 2016).”
BackgroundThe senescence-associated secretory phenotype in ovarian cancer dissemination
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Self-citationMorales-Valencia, J., & David, G. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.747822 · Cited by 21
“the DDR (96) and BRD4 inhibition, which prevents the activation of super-enhancers controling SASP genes’ transcription (97).”
BackgroundTurano, P. S., Akbulut, E., Dewald, H. K., Vasilopoulos, T., Fitzgerald-Bocarsly, P., Herbig, U., & Martínez-Zamudio, R. I. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116795 · Cited by 16
“5,6 However, the immune system’s capacity to remove senescent cells from tissues decreases with age.”
Cellular Models of Aging and Senescence
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“Furthermore, recent studies using ATAC-seq and ChIP-seq have revealed tissue-specific aging signatures [24–26], metabolic scarring/memory in diabetic cells [27,28], inflammatory priming and trained immunity affecting SASP intensity [29], and inflammatory memory [30].”
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“Bromodomain and extra-terminal domain (BET) protein inhibitors, for example, attenuate SASP transcription by disrupting BRD4-dependent enhancer activation 54 and reduce fibrosis in preclinical models 251,252 , although dose-limiting toxicities have constrained their clinical utility 253-256 .”
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“…layers of regulation, including transcription, epigenetic regulation, mRNA stability, translation, and protein stability (Herranz et al. 2015; Kang et al. 2015; Laberge et al. 2015; Tasdemir et al. 2016; Hernandez-Segura et al. 2018; Birch and Gil 2020; Sofiadis et al. 2021; Wiley et al. 2021).”
BackgroundRecent Advances in Senolysis for Age-Related Diseases
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Autophagy-dependent splicing control directs translation toward inflammation during senescence
Kim, J., Lee, Y., Jeon, T., Ju, S., Kim, J., Kim, M.-S., & Kang, C. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.10.008 · Cited by 19
Francica, P., Aebersold, D. M., & Medová, M. (2016) · Biochemical Pharmacology · doi:10.1016/j.bcp.2016.08.022 · Cited by 15
Pan, Y., Gu, Z., Lyu, Y., Yang, Y., Chung, M., Pan, X., & Cai, S. (2022) · Rejuvenation Research · doi:10.1089/rej.2022.0021 · Cited by 15
“36 This study suggests that remodeling of the enhancer landscape correlates well with SASP gene expression.”
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“[88] found that BRD4 binds to super-enhancer regions adjacent to pivotal SASP genes, thereby promoting SASP.”
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“Nonetheless, the suppression of BRD4 has been associated with the induction of senescence across various cell types, including chondrocytes [19].”
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“When this stage begins to decline, a more pro-inflammatory stage follows, during which cytokines and inflammatory mediators are robustly expressed, leading to enhanced immune surveillance and clearance of senescent cells (Tasdemir et al., 2016; Ovadya et al., 2018; Prata et al., 2018; Desdin-Mico et al., 2020).”
BackgroundBRD4 inhibition leads to MDSC apoptosis and enhances checkpoint blockade therapy
Savardekar, H., Stiff, A. R., Liu, A., Wesolowski, R., Schwarz, E. J., Garbarine, I. C., Duggan, M. C., Zelinskas, S., Li, J., Lapurga, G., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci181975 · Cited by 13
“BRD4 also regulates inflammatory responses, and studies have suggested BRD4 plays a role in regulating tumor-associated inflammation and immune responses (5–7).”
InfluentialZhou, L., DeMarco, K. D., Murphy, K. C., Wu, Z., Li, J., Johnson, C., Liu, B., Giwa, H. K., Ma, B., Bhalerao, N., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-1212 · Cited by 18
Kelly, N. J., & Chan, S. Y. (2022) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2311378 · Cited by 14
“Interestingly, BRD4 inhibition has been shown to modulate the SASP in cancer cells, potentially contributing to its efficacy in preclinical PH [186].”
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Ji, Y., Li, B., Lin, R., Yuan, J. T., Han, Y., Du, Y., & Zhao, Y. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06098-x · Cited by 14
“This impairs the cells’ ability to be removed from the body [116].”
Wu, D., Pepowski, B., Takahashi, S., & Kron, S. J. (2019) · BMC Genomics · doi:10.1186/s12864-019-5653-x · Cited by 14
Valinciute, G., Weigel, C., Veldwijk, M. R., Oakes, C. C., Herskind, C., Wenz, F. K., Plass, C., Schmezer, P., & Popanda, O. (2017) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2017.08.028 · Cited by 13
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“It is then phosphorylated by recruiting positive transcription elongation factor b (p-TEFb), thereby activating RNA polymerase II (RNA-Pol II) to directly promote transcription initiation and elongation [25, 26].”
BackgroundChem-CRISPR/dCas9FCPF: a platform for chemically induced epigenome editing
Altinbay, M., Wang, J., Chen, J., Schäfer, D., Sprang, M., Blagojevic, B., Wölfl, S., Andrade-Navarro, M. A., Đikić, I., Knapp, S., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae798 · Cited by 14
“Notably, JQ1 effectively re-pressed these BRD4-targeting genes, including FOS and JUN, two well-established downstream targets of BRD4 that significantly contribute to the on-target toxicity observed with JQ1 in clinical trials (Figure 2 H) ( 53 ,54 ).”
BackgroundIncreased chromatin accessibility underpins senescence
Lopes‐Paciencia, S., & Ferbeyre, G. (2025) · FEBS Journal · doi:10.1111/febs.70136 · Cited by 18
“Writer Reader Eraser reader of H3K9ac, which is required for the expression of the senescence-associated secretory phenotype (SASP) genes in senescent cells [25,26].”
Floros, K. V., Fairchild, C. K., Li, J., Zhang, K., Roberts, J. L., Kurupi, R., Paudel, D., Xing, Y., Hu, B., Kraskauskiene, V., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64665-8 · Cited by 12
Self-citationCellular senescence and abdominal aortic aneurysm: From pathogenesis to therapeutics
Wang, D., Hao, X., Jia, L., Jing, Y., Jiang, B., & Xin, S. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.999465 · Cited by 14
“Epigenetic regulation: Bromine domain and extra-terminal (BET) family protein BRD4 recruited the super enhancer element adjacent to SASP gene, resulting in the remodeling of the enhancer (52).”
BackgroundInterfering with bromodomain epigenome readers as therapeutic option in mucoepidermoid carcinoma
Markman, R. L., Webber, L. P., Filho, C., dos Reis, L. A., Vargas, P. A., Lopes, M. A., Zanella, V. G., Martins, M. D., SQUARIZE, C. H., & CASTILHO, R. M. (2018) · Cellular Oncology · doi:10.1007/s13402-018-0416-2 · Cited by 12
Reyes, J., Priore, I. S. D., Chaikovsky, A. C., Pasnuri, N., Elhossiny, A. M., Park, J., Weiler, P., Krause, T., Moorman, A. R., Snopkowski, C., et al. (2026) · Cell · doi:10.1016/j.cell.2026.03.032 · Cited by 12
Self-citationMitochondrial metabolism and epigenetic crosstalk drive SASP
Martini, H., Birch, J., Marques, F. M., Victorelli, S. G., Lagnado, A. B., Pirius, N., Franco, A. C., Lee, G., Han, Y., Rowsey, J. L., et al. (2026) · Nature · doi:10.1038/s41586-026-10791-2 · Cited by 18
“Previous work has shown that many SASP-associated genes are linked to super-enhancer-like regions that are particularly sensitive to changes in histone acetylation 28 .”
Systematic transcriptomic analysis and temporal modelling of human fibroblast senescence
Scanlan, R.-L., Pease, L., O’Keefe, H., Guimera, A. M., Rasmussen, L. J., Wordsworth, J., & Shanley, D. P. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1448543 · Cited by 11
Nanomaterials intervene in cell senescence to reinforce cancer therapy
Sun, S., Yang, N., Nie, J., Yang, Z., Pei, Z., Ding, R., & Cheng, L. (2025) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2025.217012 · Cited by 10
Interrogating the regulatory epigenome of cellular senescence
Thanos, D.-F., Ntintas, O. A., Athanasiadis, E. I., Papaspyropoulos, A., Petty, R., & Gorgoulis, V. G. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05848-w · Cited by 10
Zumerle, S., & Alimonti, A. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0540-x · Cited by 10
Convergent evolution of senescent fibroblasts in fibrosis and cancer with aging
Lee, J. Y., & Peng, T. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.10.002 · Cited by 12
Jin, W. Z., Jiang, S., Liu, X., He, Y., Li, T., Ma, J., Chen, Z., Lu, X., Liu, X., Shou, W., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54338-3 · Cited by 9
Wang, Z., Chen, C., Ai, J., Gao, Y., Wang, L., Xia, S., Jia, Y., & Qin, Y. (2025) · MedComm · doi:10.1002/mco2.70048 · Cited by 12
Self-citationKang, J. H., Splinter, P. L., Trussoni, C. E., Pirius, N., Gores, G. J., LaRusso, N. F., & O’Hara, S. P. (2023) · Gastroenterology · doi:10.1053/j.gastro.2023.03.235 · Cited by 9
TEAD4 antagonizes cellular senescence by remodeling chromatin accessibility at enhancer regions
Zhang, D., Zhu, Y., Ju, Y., Zhang, H., Zou, X., She, S., Zhu, D., & Guan, Y. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04980-9 · Cited by 8
“In another example, the suppression of high mobility group box 2 (HMGB2) can disrupt the chromatin landscape of SASP factors by allowing the spread of repressive heterochromatin into gene loci [26]; therefore, the control of gene expression profiles by the modulation of chromatin accessibility may…”
BackgroundMZ1, a BRD4 inhibitor, exerted its anti-cancer effects by suppressing SDC1 in glioblastoma
Li, G. L., Ma, L., Feng, C., Yin, H., Bao, J., Wu, D., Zhang, Z., Li, X., Li, Z., Yang, C., et al. (2024) · BMC Cancer · doi:10.1186/s12885-024-11966-8 · Cited by 10
“Notably, this regulatory mechanism is prominently focused on governing genes linked with SEs [14, 15].”
BackgroundWu, Q., Zheng, Q., Yuan, L., Gao, D., Hu, Y., Jiang, X., Zhai, Q., Liu, M., Xu, L., Xu, H., et al. (2024) · Cell Cycle · doi:10.1080/15384101.2024.2342714 · Cited by 8
“Concurrently, research indicates that immune-mediated clearance of senescent cells holds substantial promise in cancer therapy [13–15].”
BackgroundWang, D., & Guan, H. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.156115 · Cited by 9
Senescent cells in systemic aging: SASP heterogeneity, immune escape, and endocrine modulation
Qoura, L. A., Churov, A. V., Maltseva, O. N., Ерусланова, К. А., & Zeng, G. (2026) · Biogerontology · doi:10.1007/s10522-026-10449-6 · Cited by 9
“Concurrently, BRD4 orchestrates the reorganization of super-enhancers to sustain senescence-associated transcriptional programs (Tasdemir et al. 2016).”
Higher-Order Chromatin Regulation of Inflammatory Gene Expression
Xu, J.-W., Ling, S., & Liu, J. (2017) · Mediators of Inflammation · doi:10.1155/2017/7848591 · Cited by 9
“Transcriptional profiling and functional studies have reported that BRD4 is required for SASP and downstream paracrine signaling [52].”
BackgroundDeng, L., Mi, J., Ruan, X., Zhang, G., Pan, Y., & Wang, R. (2022) · Mediators of Inflammation · doi:10.1155/2022/4007469 · Cited by 8
Could senescence phenotypes strike the balance to promote tumor dormancy?
Chiu, F.-Y., Kvadas, R. M., Mheidly, Z., Shahbandi, A., & Jackson, J. G. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10089-z · Cited by 8
“This cytokine production by senescent cells was controlled by NF-kB activation [50], as well as BRD4-mediated chromatin remodeling [51].”
BackgroundNon-oncogene dependencies: Novel opportunities for cancer therapy
Marco, T. D., Mazzoni, M., Greco, A., & Cassinelli, G. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116254 · Cited by 9
Dynamic enhancer interactome promotes senescence and agingPreprint
Wang, L., Donahue, G., Zhang, C., Havas, A. P., Lei, X., Xu, C., Wang, W., Vahedi, G., Adams, P. D., & Berger, S. L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.22.541769 · Cited by 8
Integrating Senescence and Oxidative Stress in Cardiac Disease
Yun, H. R., Singh, M. K., Han, S., Ranbhise, J. S., Ha, J., Kim, S. S., & Kang, I. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262411917 · Cited by 8
“…[45], Janus kinase 1 and 2 (JAK1/2) blockade [46], bromodomain and extraterminal (BET)-bromodomain- containing protein 4 (BRD4) inhibition [47], p38-mitogen-activated protein kinase (MAPK) to MAPK-activated protein kinase 2 (MK2) pathway inhibition [27], or blockade of cyclic GMP-AMP…”
Engineering brain-penetrant PROTACs: Bridging molecular design and CNS delivery
Li, X., Li, J., Sun, Y., Yao, T., Lu, Y., Liu, S., Li, H., Shi, Y., Chen, L., Zhao, Y., et al. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115876 · Cited by 8
Senescence-associated genes and non-coding RNAs function in pancreatic cancer progression
Cheng, Q., Ouyang, X., Zhang, R., Zhu, L., & Song, X. (2020) · RNA Biology · doi:10.1080/15476286.2020.1719752 · Cited by 7
“Replicative senescence datasets GSE74324 (IMR90) [66], GSE63577 (IMR90, WI38 and BJ) [67,68] and GSE53356 (IMR90) [69] were employed for senescent validations.”
MethodTargeting the stress support network regulated by autophagy and senescence for cancer treatment
Kim, J., Lee, Y., Roh, K., Kim, M.-S., & Kang, C. (2021) · Advances in cancer research · doi:10.1016/bs.acr.2021.01.003 · Cited by 7
HDAC3 regulates senescence and lineage specificity in non-small cell lung cancerPreprint
Eichner, L. J., Curtis, S. D., Brun, S. N., Baumgart, J. T., Ross, D. S., Rymoff, T. J., & Shaw, R. J. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.14.338590 · Cited by 6
“The crystal structure also unexpectedly revealed the presence of inositol tetra phosphate (Ins(1,4,5,6)P4 or IP4), which serves as an ‘intermolecular glue’ by forming hydrogen bonds and salt bridges54 between the two proteins (FIG.”
BackgroundInfluentialCantarella, S., Vezzoli, M., Carnevali, D., Morselli, M., Zemke, N. R., Montanini, B., Daussy, C. F., Wodrich, H., Teichmann, M., Pellegrini, M. A., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae615 · Cited by 6
“We thus further focused on publicly available CEBPB, FOS, YAP1 and BRD4 ChIP-seq data in IMR90 cells ( 75–79 ).”
MethodLocal and systemic impact of adipocyte senescence-associated secretory profile
Wan, Y. C. E., Dufau, J., & Spalding, K. L. (2024) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2024.100547 · Cited by 8
Zhang, G., Li, L., Yang, Z., Cao, Z., Hu, X., Wang, Y., & Kang, X. (2025) · Aging Cell · doi:10.1111/acel.70034 · Cited by 6
“Tasdemir et al. (2016) demonstrated that BRD4 downregulation reduces senescence in human fibroblasts by inhibiting the expression of SASP-related molecules.”
Proteomic Profiles of Neutrophils from Behcet’s Uveitis Patients and their Sex Differences
Liu, R., Wang, Q., Jiang, Q., Chang, R., Zhou, Y., Ye, X., Luo, X., Lai, Y., Su, G., & Yang, P. (2025) · Inflammation · doi:10.1007/s10753-025-02305-5 · Cited by 6
Transcription factor network dynamics during the commitment to oncogene-induced senescence
Vasilopoulos, T., & Martínez‐Zamudio, R. I. (2024) · Frontiers in Epigenetics and Epigenomics · doi:10.3389/freae.2024.1423454 · Cited by 5
Senescence Can Be BETter without the SASP?
Vizioli, M. G., & Adams, P. D. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0485 · Cited by 6
“Tasdemir and colleagues (4) shed light on this matter by establishing a new player underlying the regulation of SASP genes that is responsible for the interplay between senescent cells and tissue microenvironment.”
BackgroundTargeting senescent cell clearance: An approach to delay aging and age-associated disorders
Qiu, Z., Jia, J., Zou, H., Ao, Y., Liu, B., & Wang, Z. (2021) · Translational Medicine of Aging · doi:10.1016/j.tma.2020.12.001 · Cited by 6
Establishing evidence for immune surveillance of β-cell senescence
Morelli, N. R., Pipella, J., & Thompson, P. J. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.01.003 · Cited by 7
Multifaceted regulation of enhancers in cancer
Xiao, Q., Xiao, Y., Li, L., Chen, M., & Wu, M. (2022) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2022.194839 · Cited by 6
AP-1 Imprints a Reversible Transcriptional Program of Senescent CellsPreprint
Martínez-Zamudio, R. I., Roux, P., de Freitas, J. A. N. L. F., Robinson, L. J., Doré, G. R. G., Sun, B., Gil, J., Herbig, U., & Bischof, O. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/633594 · Cited by 6
O-GlcNAcylation of FOXK1 orchestrates the E2F pathway and promotes oncogenesis
Masclef, L., Ahmed, O., Iannantuono, N., Gagnon, J., Gushul-Leclaire, M., Boulay, K., Estavoyer, B., Echbicheb, M., Poy, M., Ali Boubacar, K., et al. (2024) · doi:10.1101/2024.03.01.582838 · Cited by 6
Ligand-specific regulation of a binary enhancer code dictating cellular senescence
Suter, T., Friedman, M. J., Tazearslan, C., Merkurjev, D., Ohgi, K., Meluzzi, D., Rosenfeld, M. G., & Suh, Y. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2506321122 · Cited by 5
“These initial observations are consistent with reported dynamic changes in enhancer usage in aging tissues (41) and senescent cells (42–44).”
Targeting super-enhancers in liver cancer: from pathogenic mechanisms to clinical applications
Li, C., Yao, Z., Sun, A., Cao, J., & Wang, Z. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1589455 · Cited by 5
Shahzaib, M., Aprile, D., Squillaro, T., Alessio, N., Peluso, G., Bernardo, G. D., & Galderisi, U. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102916 · Cited by 6
Ho, C. Z., Deng, L., Picone, R., Abderazzaq, F. O., Flanagan, N., Chua, D. Z., Low, B. C., & Wu, S. K. (2025) · Molecular Biology of the Cell · doi:10.1091/mbc.e24-10-0445 · Cited by 5
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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