BRD4 connects enhancer remodeling to senescence immune surveillance

Nilgun Tasdemir, Ana Banito, Jae Seok Roe, Direna Alonso-Curbelo, Matthew Camiolo, Darjus F. Tschaharganeh, Chun Hao Huang, Ozlem Aksoy, Jessica E. Bolden, Chi Chao Chen, Myles Fennell, Vishal Thapar, Agustin Chicas, Christopher R. Vakoc, Scott W. Lowe

Research output: Contribution to journalArticle

97 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)613-629
Number of pages17
JournalCancer Discovery
Volume6
Issue number6
DOIs
Publication statusPublished - 2016 Jun

All Science Journal Classification (ASJC) codes

  • Oncology

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    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. (2016). BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discovery, 6(6), 613-629. https://doi.org/10.1158/2159-8290.CD-16-0217