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.
Bibliographical noteFunding Information:
This study was supported by funds from an R01 grant (AG16379) from the NIH (to S.W. Lowe), CA013106 (NIH/NCI), and NIH/NCI Cancer Center Support Grant P30 CA008748. N. Tasdemir was supported by the Lindsay and Goldberg Fellowship from the Watson School of Biological Sciences. A. Banito was supported by an EMBO long-term fellowship. D. Alonso-Curbelo is recipient of a postdoctoral fellowship from the Spanish Fundación Ramón Areces. J.-S. Roe is supported by the Martin Sass Foundation and the Lauri Strauss Leukemia Foundation. S.W. Lowe is an investigator at the Howard Hughes Medical Institute and is the Geoffrey Beene Chair of Cancer Biology.
© 2016 American Association for Cancer Research.
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