期刊
CANCER DISCOVERY
卷 6, 期 6, 页码 612-629出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-16-0217
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资金
- R01 grant from the NIH [AG16379]
- NIH/NCI Cancer Center [P30 CA008748]
- Lindsay and Goldberg Fellowship from the Watson School of Biological Sciences
- Spanish Fundacion Ramon Areces
- Martin Sass Foundation
- Lauri Strauss Leukemia Foundation
- EMBO long-term fellowship
- NIH/NCI [CA013106]
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. (C) 2016 AACR.
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