CCAR2 acetylation establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition Academic Article uri icon


  • Abstract There continues to be interest in targeting epigenetic readers, writers and erasers for the treatment of cancer and other pathologies. A mechanistic understanding is frequently lacking, however, for the synergy observed when combining deacetylase and bromodomain inhibitors. We identified cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane (SFN). N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 (HDAC3) and -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. The BET inhibitor JQ1 synergized with SFN in colon cancer cells, and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with SFN+JQ1 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. These results highlight the competition that exists among the readers of acetylated histone and non-histone proteins, and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments. Citation Format: Gavin S. Johnson, Praveen Rajendran, Li Li, Ying-Shiuan Chen, W. Mohaiza Dashwood, Nhung Nguyen, Ahmet M. Ulusan, Furkan Ertem, Mutian Zhang, Deqiang Sun, Yun Huang, Shan Wang, Hon-Chiu E. Leung, David Lieberman, Laura M. Beaver, Emily Ho, Mark T. Bedford, Kyle Chang, Eduardo Vilar, Roderick H. Dashwood. CCAR2 acetylation establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2614.

published proceedings


author list (cited authors)

  • Johnson, G. S., Rajendran, P., Li, L. i., Chen, Y., Dashwood, W. M., Nhung, N., ... Dashwood, R. H.

citation count

  • 0

complete list of authors

  • Johnson, Gavin S||Rajendran, Praveen||Li, Li||Chen, Ying-Shiuan||Dashwood, W Mohaiza||Nhung, Nguyen||Ulusan, Ahmet M||Ertem, Furkan||Zhang, Mutian||Sun, Deqiang||Huang, Yun||Wang, Shan||Leung, Hon-Chiu E||Lieberman, David||Beaver, Laura M||Ho, Emily||Bedford, Mark T||Chang, Kyle||Vilar, Eduardo||Dashwood, Roderick H

publication date

  • July 2019