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.
Highlights
Epigenetic regulation has been broadly defined as alteration of gene expression through chromatin structure modification without changing the underlying nucleotide sequences [1]
The endogenous binding activity of intestine-specific homeobox (ISX) on promoters of epithelial–mesenchymal transition (EMT) markers was verified by Chromatin Immunoprecipitation (ChIP), and the results showed endogenous ISX bound directly to the promoters of genes involved in EMT, and IL6 promoted the promoter-binding activity of ISX (Fig 1G)
These results suggested that ISX expression transcriptionally upregulated EMT regulators and promoted EMT characteristics in lung cancer cells
Summary
Epigenetic regulation has been broadly defined as alteration of gene expression through chromatin structure modification without changing the underlying nucleotide sequences [1]. A type of epigenetic modification, plays an important role in gene regulation during embryonic development and human disease progression [2]. As an organizer of super-enhancers (SEs) of hyper-acetylated promoter nucleosomes through a bromodomain-mediated recruitment mechanism, BRD4 has been shown to interact with TFs that facilitate downstream gene expression [14,15], including oncogenes [12]. Genome-wide studies have indicated that BRD4 is widely distributed along the genome, selective gene expression patterns and how recruitment of HAT-containing co-activators to specific promoters modulates TF-associated nucleosome organization remain largely undefined. The present study shows that PCAF acetylation of intestine-specific homeobox (ISX) recruits BRD4 to promoter nucleosome movement at EMT initiator, such as TWIST1 and Snail, thereby facilitating chromatin remodeling and transcriptional initiation via histone H3 acetylation. Ectopic expression of PCAF–ISX–BRD4 axis components correlates with clinical metastatic features and poor prognosis, suggesting that the PCAF–ISX–BRD4 axis is an important regulator of tumor metastasis and cell plasticity in a tumorigenic microenvironment
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