TY - JOUR
T1 - PCAF-mediated acetylation of ISX recruits BRD4 to promote epithelial-mesenchymal transition
AU - Wang, Li Ting
AU - Liu, Kwei Yan
AU - Jeng, Wen Yih
AU - Chiang, Cheng Ming
AU - Chai, Chee Yin
AU - Chiou, Shyh Shin
AU - Huang, Ming Shyang
AU - Yokoyama, Kazunari K.
AU - Wang, Shen Nien
AU - Huang, Shau Ku
AU - Hsu, Shih Hsien
N1 - Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2020/2/5
Y1 - 2020/2/5
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85078073978&partnerID=8YFLogxK
U2 - 10.15252/embr.201948795
DO - 10.15252/embr.201948795
M3 - Article
C2 - 31908141
AN - SCOPUS:85078073978
SN - 1469-221X
VL - 21
JO - EMBO Reports
JF - EMBO Reports
IS - 2
M1 - e48795
ER -