@article{207375d8b89f4c1fbc01d35d8238781b,
title = "Acetylation of CCAR2 establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition",
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 sulforaphane{\th}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. 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.",
author = "Praveen Rajendran and Gavin Johnson and Li Li and Chen, {Ying Shiuan} and Mohaiza Dashwood and Nhung Nguyen and Ahmet Ulusan and Furkan Ertem and Mutian Zhang and Jia Li and Deqiang Sun and Yun Huang and Shan Wang and Leung, {Hon Chiu} and David Lieberman and Laura Beaver and Emily Ho and Mark Bedford and Kyle Chang and Eduardo Vilar and Roderick Dashwood",
note = "Funding Information: We thank R. Jaimes, L. Chew, and A. Khan for technical assistance. Dr. O. Hiraike (University of Tokyo, Japan) provided a Myc-DBC expression construct, whereas plasmids pE312 (pPB 4xU25C EF1 AcKRS-TAGT2A-Dendra2 IRES Puro) and pE337 (pPB 4xU25C EF1 H33 3xHA IRES Neo) were from Dr. J. Chin (MRC Laboratory of Molecular Biology, Cambridge, UK). Protein arrays were run by C. Sagum in the Protein Array and Analysis Core, supported by Cancer Prevention & Research Institute of Texas grant no. RP130432. L.M. Lui provided technical help with mass spectrometry (Protein Mass Spectrometry Core, Baylor College of Medicine), and N. Otto performed IHC in the MD Anderson Pathology & Imaging Core. Initial RNA-seq was conducted at the Center for Genome Research and Biocomputing at Oregon State University (Corvallis, OR). This work was supported by grants CA090890 and CA122959 from the NCI, the John S. Dunn Foundation, and a Chancellor's Research Initiative. Funding also was provided by grants R25TCA057730, CA208461, and CA016672 and a gift from the Feinberg Family to E. Vilar. Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",
year = "2019",
month = mar,
day = "1",
doi = "10.1158/0008-5472.CAN-18-2003",
language = "English (US)",
volume = "79",
pages = "918--927",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "5",
}