@article{1fbeabbd412444bfa3886e7ccd291ca0,
title = "PCAF-mediated acetylation of ISX recruits BRD4 to promote epithelial-mesenchymal transition",
abstract = "Epigenetic regulation is important for cancer progression; however, the underlying mechanisms, particularly those involving protein acetylation, remain to be fully understood. Here, we show that p300/CBP-associated factor (PCAF)-dependent acetylation of the transcription factor intestine-specific homeobox (ISX) regulates epithelial–mesenchymal transition (EMT) and promotes cancer metastasis. Mechanistically, PCAF acetylation of ISX at lysine 69 promotes the interaction with acetylated bromodomain-containing protein 4 (BRD4) at lysine 332 in tumor cells, and the translocation of the resulting complex into the nucleus. There, it binds to promoters of EMT genes, where acetylation of histone 3 at lysines 9, 14, and 18 initiates chromatin remodeling and subsequent transcriptional activation. Ectopic ISX expression enhances EMT marker expression, including TWIST1, Snail1, and VEGF, induces cancer metastasis, but suppresses E-cadherin expression. In lung cancer, ectopic expression of PCAF–ISX–BRD4 axis components correlates with clinical metastatic features and poor prognosis. These results suggest that the PCAF–ISX–BRD4 axis mediates EMT signaling and regulates tumor initiation and metastasis.",
keywords = "BRD4, EMT, ISX, TWIST1",
author = "Wang, {Li Ting} and Liu, {Kwei Yan} and Jeng, {Wen Yih} and Chiang, {Cheng Ming} and Chai, {Chee Yin} and Chiou, {Shyh Shin} and Huang, {Ming Shyang} and Yokoyama, {Kazunari K.} and Wang, {Shen Nien} and Huang, {Shau Ku} and Hsu, {Shih Hsien}",
note = "Funding Information: We are grateful for the supporting from the Bio‐Bank, Medical Research Department, E‐DA Hospital, Taiwan. This work was supported in part by research grants KMUH 106‐6R33, KMUH107‐7R46, and KMUH107‐7R34 from the Kaohsiung Medical University Hospital, Kaohsiung Medical University Research Center Grant (KMU‐TC108A04‐5) and MOST‐105‐2314‐B‐037‐70‐MY2, MOST‐106‐2314‐B‐037‐090‐MY2, MOST‐107‐2314‐B‐037‐063‐MY3, MOST‐107‐2314‐B‐037‐028‐MY3, MOST‐108‐2320‐B‐037‐005, and MOST‐108‐2314‐B‐037‐065‐MY3 from the Ministry of Science and Technology, Taiwan (MOST), Kaohsiung Medical University (KMU) grant (KMU‐DK108012; KMU‐TC108A02), National Health Research Institutes (NHRI), Taiwan (EOPP10‐014; NHRI‐EX108‐10720SI); Kaohsiung Medical University “The Talent Plan” (106KMUOR04), Taiwan; and Shenzhen Science and Technology Peacock Team Project (KQTD20170331145453160). C.‐M.C. is supported by US National Institutes of Health (NIH RO1CA103867), Cancer Prevention & Research Institute of Texas (CPRIT RP180349 and RP190077), and Welch Foundation (I‐1805). Publisher Copyright: {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2020",
month = feb,
day = "5",
doi = "10.15252/embr.201948795",
language = "English",
volume = "21",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "2",
}