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.

• Authors: Li-Ting Wang, Kwei-Yan Liu, Wen-Yih Jeng, Cheng-Ming Chiang, Chee-Yin Chai, Shyh-Shin Chiou, Ming-Shyang Huang, Kazunari K Yokoyama, Shen-Nien Wang, Shau-Ku Huang, Shih-Hsien Hsu
• Journal: EMBO reports (EMBO Rep) Vol. 21 Issue 2 Pg. e48795 (02 05 2020) ISSN: 1469-3178 [Electronic] England
• PMID: 31908141 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Nuclear Proteins
• Transcription Factors
• p300-CBP Transcription Factors

Topics

• Acetylation
• Epigenesis, Genetic
• Epithelial-Mesenchymal Transition (genetics)
• Genes, Homeobox
• Humans
• Neoplasms
• Nuclear Proteins (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• p300-CBP Transcription Factors (metabolism)