BRD4 connects enhancer remodeling to senescence immune surveillance

Tasdemir, N., Banito, A., Roe, J. S., Alonso-Curbelo, D., Camiolo, M., Tschaharganeh, D. F., Huang, C. H., Aksoy, O., Bolden, J. E., Chen, C. C., Fennell, M., Thapar, V., Chicas, A., Vakoc, C. R., Lowe, S. W. (June 2016) BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov, 6 (6). pp. 612-629. ISSN 2159-8290 (Electronic)2159-8274 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/27099234
DOI: 10.1158/2159-8290.cd-16-0217

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > BET bromodomain coactivator protein > Brd4
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:
Communities: CSHL labs > Lowe lab
CSHL labs > Vakoc lab
Depositing User: Matt Covey
Date: June 2016
Date Deposited: 26 Apr 2016 19:31
Last Modified: 01 Jul 2016 16:56
PMCID: PMC4893996
Related URLs:
URI: http://repository.cshl.edu/id/eprint/32617

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