BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance.
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.



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.
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.
Nilgun
N
Tasdemir
Memorial Sloan Kettering Cancer Center, New York, New York.
Ana
A
Banito
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
Jae-Seok
JS
Roe
Memorial Sloan Kettering Cancer Center, New York, New York.
Direna
D
Alonso-Curbelo
Medical Scientist Training Program, Stony Brook University, Stony Brook, New York.
Matthew
M
Camiolo
Memorial Sloan Kettering Cancer Center, New York, New York.
Darjus F
DF
Tschaharganeh
Memorial Sloan Kettering Cancer Center, New York, New York. Weill Graduate School of Medical Sciences, Cornell University, New York, New York.
Chun-Hao
CH
Huang
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.
Ozlem
O
Aksoy
Memorial Sloan Kettering Cancer Center, New York, New York.
Jessica E
JE
Bolden
Memorial Sloan Kettering Cancer Center, New York, New York. Weill Graduate School of Medical Sciences, Cornell University, New York, New York.
Chi-Chao
CC
Chen
Memorial Sloan Kettering Cancer Center, New York, New York.
Myles
M
Fennell
Memorial Sloan Kettering Cancer Center, New York, New York.
Vishal
V
Thapar
Memorial Sloan Kettering Cancer Center, New York, New York.
Agustin
A
Chicas
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. lowes@mskcc.org vakoc@cshl.edu.
Christopher R
CR
Vakoc
Memorial Sloan Kettering Cancer Center, New York, New York. Howard Hughes Medical Institute, New York, New York. lowes@mskcc.org vakoc@cshl.edu.
Scott W
SW
Lowe
D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D007157:Immunologic Surveillance / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D059372:Nucleotide Motifs; D009857:Oncogenes; D019899:Paracrine Communication; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D020558:GTP Phosphohydrolases; D006657:Histones; D008565:Membrane Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C579846:NRAS protein, human