PCAF ‐mediated acetylation of ISX recruits BRD 4 to promote epithelial‐mesenchymal transition

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.