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)
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 Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Lowe lab CSHL labs > Vakoc lab School of Biological Sciences > Publications |
| Depositing User: | Matt Covey |
| Date: | June 2016 |
| Date Deposited: | 26 Apr 2016 19:31 |
| Last Modified: | 01 Mar 2024 15:15 |
| PMCID: | PMC4893996 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/32617 |
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