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

• Published in: EMBO reports 2020-02, Vol.21 (2), p.e48795-n/a
• Main Authors: Wang, Li‐Ting, Liu, Kwei‐Yan, Jeng, Wen‐Yih, Chiang, Cheng‐Ming, Chai, Chee‐Yin, Chiou, Shyh‐Shin, Huang, Ming‐Shyang, Yokoyama, Kazunari K, Wang, Shen‐Nien, Huang, Shau‐Ku, Hsu, Shih‐Hsien
• Format: Article
• Language: English
• Subjects: Acetylation; BRD4; Cancer; Chromatin remodeling; Complex formation; Ectopic expression; EMBO03; EMBO09; EMBO31; EMT; Epigenesis, Genetic; Epithelial-Mesenchymal Transition - genetics; Event-related potentials; Genes; Genes, Homeobox; Homeobox; Humans; Intestine; ISX; Kinases; Lung cancer; Lysine; Mesenchyme; Metastases; Metastasis; Neoplasms; Non-small cell lung carcinoma; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclei (cytology); p300-CBP Transcription Factors - metabolism; Prognosis; Proteins; Regulators; Transcription activation; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Translocation; Tumor cells; Tumors; TWIST1; Vascular endothelial growth factor
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201948795

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. Synopsis The PCAF–ISX–BRD4 axis is an important regulator of tumor metastasis and cell plasticity. PCAF‐mediated acetylation of the transcription factor ISX promotes translocation of ISX‐BRD4 to the nucleus to activate EMT genes and to induce metastasis. ISX transactivates genes encoding EMT regulators and promotes EMT. PCAF acetylation of ISX is essential for ISX–BRD4 complex formation, and induces EMT and cancer cell metastasis. PCA, ISX and BRD4 show high expression correlation with clinical outcomes and prognosis in patients with NSCLC. Graphical Abstract The PCAF–ISX–BRD4 axis is an important regulator of tumor metastasis and cell plasticity. PCAF‐mediated acetylation of the transcription factor ISX promotes translocation of ISX‐BRD4 to the nucleus to activate EMT genes and to induce metastasis.