한빛사 논문
Abstract
Nilgun Tasdemir1,5, Ana Banito1,5, Jae-Seok Roe2,5, Direna Alonso-Curbelo1,5, Matthew Camiolo3, Darjus F. Tschaharganeh4, Chun-Hao Huang1, Ozlem Aksoy1, Jessica E. Bolden1, Chi-Chao Chen1, Myles Fennell1, Vishal Thapar1, Agustin Chicas1, Christopher R. Vakoc2,* and Scott W. Lowe1,*
1Memorial Sloan Kettering Cancer Center
2Cold Spring Harbor Laboratory
3Medical Scientist Training Program, Stony Brook University
4Memorial Sloan-Kettering Cancer Center
5These authors contributed equally to this work.
* Corresponding Authors.
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.
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