Acetylation of CCAR2 establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition

Praveen Rajendran, Gavin Johnson, Li Li, Ying Shiuan Chen, Mohaiza Dashwood, Nhung Nguyen, Ahmet Ulusan, Furkan Ertem, Mutian Zhang, Jia Li, Deqiang Sun, Yun Huang, Shan Wang, Hon Chiu Leung, David Lieberman, Laura Beaver, Emily Ho, Mark T Bedford, Kyle Chang, Eduardo Vilar Sanchez & 1 others Roderick Dashwood

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

There continues to be interest in targeting epigenetic "readers, writers, and erasers" for the treatment of cancer and other pathologies. However, a mechanistic understanding is frequently lacking for the synergy observed when combining deacetylase and bromodomain inhibitors. Here we identify cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane. N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 and b-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl "reader" proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. Treatment with the BET inhibitor JQ1 synergized with sulforaphane in colon cancer cells and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with sulforaphaneþJQ1 in combination implicated a BET/BRD9 acetyl switch and a shift in the pool of acetyl "reader" proteins in favor of BRD9-regulated target genes. Significance: These results highlight the competition that exists among the "readers" of acetylated histone and nonhistone proteins and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments.

Original languageEnglish (US)
Pages (from-to)918-927
Number of pages10
JournalCancer Research
Volume79
Issue number5
DOIs
StatePublished - Mar 1 2019

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Acetylation
Cell Cycle
Apoptosis
Epigenomics
Colonic Neoplasms
Catenins
Protein Array Analysis
Cell Cycle Proteins
Histones
Colorectal Neoplasms
Neoplasms
Proteins
Pathology
Genes
sulforafan
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rajendran, P., Johnson, G., Li, L., Chen, Y. S., Dashwood, M., Nguyen, N., ... Dashwood, R. (2019). Acetylation of CCAR2 establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition. Cancer Research, 79(5), 918-927. https://doi.org/10.1158/0008-5472.CAN-18-2003

Acetylation of CCAR2 establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition. / Rajendran, Praveen; Johnson, Gavin; Li, Li; Chen, Ying Shiuan; Dashwood, Mohaiza; Nguyen, Nhung; Ulusan, Ahmet; Ertem, Furkan; Zhang, Mutian; Li, Jia; Sun, Deqiang; Huang, Yun; Wang, Shan; Leung, Hon Chiu; Lieberman, David; Beaver, Laura; Ho, Emily; Bedford, Mark T; Chang, Kyle; Vilar Sanchez, Eduardo; Dashwood, Roderick.

In: Cancer Research, Vol. 79, No. 5, 01.03.2019, p. 918-927.

Research output: Contribution to journalArticle

Rajendran, P, Johnson, G, Li, L, Chen, YS, Dashwood, M, Nguyen, N, Ulusan, A, Ertem, F, Zhang, M, Li, J, Sun, D, Huang, Y, Wang, S, Leung, HC, Lieberman, D, Beaver, L, Ho, E, Bedford, MT, Chang, K, Vilar Sanchez, E & Dashwood, R 2019, 'Acetylation of CCAR2 establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition' Cancer Research, vol. 79, no. 5, pp. 918-927. https://doi.org/10.1158/0008-5472.CAN-18-2003
Rajendran, Praveen ; Johnson, Gavin ; Li, Li ; Chen, Ying Shiuan ; Dashwood, Mohaiza ; Nguyen, Nhung ; Ulusan, Ahmet ; Ertem, Furkan ; Zhang, Mutian ; Li, Jia ; Sun, Deqiang ; Huang, Yun ; Wang, Shan ; Leung, Hon Chiu ; Lieberman, David ; Beaver, Laura ; Ho, Emily ; Bedford, Mark T ; Chang, Kyle ; Vilar Sanchez, Eduardo ; Dashwood, Roderick. / Acetylation of CCAR2 establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition. In: Cancer Research. 2019 ; Vol. 79, No. 5. pp. 918-927.
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AU - Chen, Ying Shiuan

AU - Dashwood, Mohaiza

AU - Nguyen, Nhung

AU - Ulusan, Ahmet

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AU - Sun, Deqiang

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