BRD4 connects enhancer remodeling to senescence immune surveillance

Nilgun Tasdemir, Ana Banito, Jae-Seok Roe, Direna Alonso-Curbelo, Matthew Camiolo, Darjus F. Tschaharganeh, Chun Hao Huang, Ozlem Aksoy, Jessica E. Bolden, Chi Chao Chen, Myles Fennell, Vishal Thapar, Agustin Chicas, Christopher R. Vakoc, Scott W. Lowe

Research output: Contribution to journalArticle

72 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)613-629
Number of pages17
JournalCancer Discovery
Volume6
Issue number6
DOIs
Publication statusPublished - 2016 Jun 1

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Phenotype
Oncogenes
Chromatin
Paracrine Communication
Genes
Neoplasms
Carcinogenesis
In Vitro Techniques
Protein Domains

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Tasdemir, N., Banito, A., Roe, J-S., Alonso-Curbelo, D., Camiolo, M., Tschaharganeh, D. F., ... Lowe, S. W. (2016). BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discovery, 6(6), 613-629. https://doi.org/10.1158/2159-8290.CD-16-0217
Tasdemir, Nilgun ; Banito, Ana ; Roe, Jae-Seok ; Alonso-Curbelo, Direna ; Camiolo, Matthew ; Tschaharganeh, Darjus F. ; Huang, Chun Hao ; Aksoy, Ozlem ; Bolden, Jessica E. ; Chen, Chi Chao ; Fennell, Myles ; Thapar, Vishal ; Chicas, Agustin ; Vakoc, Christopher R. ; Lowe, Scott W. / BRD4 connects enhancer remodeling to senescence immune surveillance. In: Cancer Discovery. 2016 ; Vol. 6, No. 6. pp. 613-629.
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Tasdemir, N, Banito, A, Roe, J-S, Alonso-Curbelo, D, Camiolo, M, Tschaharganeh, DF, Huang, CH, Aksoy, O, Bolden, JE, Chen, CC, Fennell, M, Thapar, V, Chicas, A, Vakoc, CR & Lowe, SW 2016, 'BRD4 connects enhancer remodeling to senescence immune surveillance', Cancer Discovery, vol. 6, no. 6, pp. 613-629. https://doi.org/10.1158/2159-8290.CD-16-0217

BRD4 connects enhancer remodeling to senescence immune surveillance. / Tasdemir, Nilgun; Banito, Ana; Roe, Jae-Seok; Alonso-Curbelo, Direna; Camiolo, Matthew; Tschaharganeh, Darjus F.; Huang, Chun Hao; Aksoy, Ozlem; Bolden, Jessica E.; Chen, Chi Chao; Fennell, Myles; Thapar, Vishal; Chicas, Agustin; Vakoc, Christopher R.; Lowe, Scott W.

In: Cancer Discovery, Vol. 6, No. 6, 01.06.2016, p. 613-629.

Research output: Contribution to journalArticle

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T1 - BRD4 connects enhancer remodeling to senescence immune surveillance

AU - Tasdemir, Nilgun

AU - Banito, Ana

AU - Roe, Jae-Seok

AU - Alonso-Curbelo, Direna

AU - Camiolo, Matthew

AU - Tschaharganeh, Darjus F.

AU - Huang, Chun Hao

AU - Aksoy, Ozlem

AU - Bolden, Jessica E.

AU - Chen, Chi Chao

AU - Fennell, Myles

AU - Thapar, Vishal

AU - Chicas, Agustin

AU - Vakoc, Christopher R.

AU - Lowe, Scott W.

PY - 2016/6/1

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N2 - 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.

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Tasdemir N, Banito A, Roe J-S, Alonso-Curbelo D, Camiolo M, Tschaharganeh DF et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discovery. 2016 Jun 1;6(6):613-629. https://doi.org/10.1158/2159-8290.CD-16-0217