Molecular mechanisms of TWIST1‐regulated transcription in EMT and cancer metastasis

Abstract

AbstractTWIST1 induces epithelial‐to‐mesenchymal transition (EMT) to drive cancer metastasis. It is yet unclear what determines TWIST1 functions to activate or repress transcription. We found that the TWIST1 N‐terminus antagonizes TWIST1‐regulated gene expression, cancer growth and metastasis. TWIST1 interacts with both the NuRD complex and the NuA4/TIP60 complex (TIP60‐Com) via its N‐terminus. Non‐acetylated TWIST1‐K73/76 selectively interacts with and recruits NuRD to repress epithelial target gene transcription. Diacetylated TWIST1‐acK73/76 binds BRD8, a component of TIP60‐Com that also binds histone H4‐acK5/8, to recruit TIP60‐Com to activate mesenchymal target genes and MYC. Knockdown of BRD8 abolishes TWIST1 and TIP60‐Com interaction and TIP60‐Com recruitment to TWIST1‐activated genes, resulting in decreasing TWIST1‐activated target gene expression and cancer metastasis. Both TWIST1/NuRD and TWIST1/TIP60‐Com complexes are required for TWIST1 to promote EMT, proliferation, and metastasis at full capacity. Therefore, the diacetylation status of TWIST1‐K73/76 dictates whether TWIST1 interacts either with NuRD to repress epithelial genes, or with TIP60‐Com to activate mesenchymal genes and MYC. Since BRD8 is essential for TWIST1‐acK73/76 and TIP60‐Com interaction, targeting BRD8 could be a means to inhibit TWIST1‐activated gene expression.