PCAF-mediated acetylation of ISX recruits BRD4 to promote epithelial-mesenchymal transition

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

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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.

Original languageEnglish
Article numbere48795
JournalEMBO Reports
Volume21
Issue number2
DOIs
Publication statusPublished - 2020 Feb 5

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Wang, L. T., Liu, K. Y., Jeng, W. Y., Chiang, C. M., Chai, C. Y., Chiou, S. S., Huang, M. S., Yokoyama, K. K., Wang, S. N., Huang, S. K., & Hsu, S. H. (2020). PCAF-mediated acetylation of ISX recruits BRD4 to promote epithelial-mesenchymal transition. EMBO Reports, 21(2), [e48795]. https://doi.org/10.15252/embr.201948795