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Cancer Discov. 2016 Jun;6(6):612-29. doi: 10.1158/2159-8290.CD-16-0217. Epub 2016 Apr 20.

BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance.

Author information

1
Memorial Sloan Kettering Cancer Center, New York, New York. Watson School of Biological Sciences, Cold Spring Harbor, New York. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
2
Memorial Sloan Kettering Cancer Center, New York, New York.
3
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
4
Medical Scientist Training Program, Stony Brook University, Stony Brook, New York.
5
Memorial Sloan Kettering Cancer Center, New York, New York. Weill Graduate School of Medical Sciences, Cornell University, New York, New York.
6
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. lowes@mskcc.org vakoc@cshl.edu.
7
Memorial Sloan Kettering Cancer Center, New York, New York. Howard Hughes Medical Institute, New York, New York. lowes@mskcc.org vakoc@cshl.edu.

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. 576This article is highlighted in the In This Issue feature, p. 561.

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PMID:
27099234
PMCID:
PMC4893996
DOI:
10.1158/2159-8290.CD-16-0217
[Indexed for MEDLINE]
Free PMC Article

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