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PCAF ‐mediated acetylation of ISX recruits BRD 4 to promote epithelial‐mesenchymal transition
Author(s) -
Wang LiTing,
Liu KweiYan,
Jeng WenYih,
Chiang ChengMing,
Chai CheeYin,
Chiou ShyhShin,
Huang MingShyang,
Yokoyama Kazunari K,
Wang ShenNien,
Huang ShauKu,
Hsu ShihHsien
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948795
Subject(s) - pcaf , acetylation , brd4 , cancer research , bromodomain , ectopic expression , transcription factor , histone , epithelial–mesenchymal transition , epigenetics , biology , metastasis , chromatin , cancer , microbiology and biotechnology , chemistry , gene , genetics
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 ( BRD 4) 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 TWIST 1, Snail1, and VEGF , induces cancer metastasis, but suppresses E‐cadherin expression. In lung cancer, ectopic expression of PCAF – ISX – BRD 4 axis components correlates with clinical metastatic features and poor prognosis. These results suggest that the PCAF – ISX – BRD 4 axis mediates EMT signaling and regulates tumor initiation and metastasis.