BRD4 connects enhancer remodeling to senescence immune surveillance Journal Article
| 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. |
| Article Title: | BRD4 connects enhancer remodeling to senescence immune surveillance |
| 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. © 2016 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 6 |
| Issue: | 6 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2016-06-01 |
| Start Page: | 612 |
| End Page: | 629 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-16-0217 |
| PROVIDER: | scopus |
| PMCID: | PMC4893996 |
| PUBMED: | 27099234 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 March 2017 -- Source: Scopus |
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