Interplay between HDAC3 and WDR5 Is Essential for Hypoxia-Induced Epithelial-Mesenchymal Transition

SummaryEpithelial-mesenchymal transition (EMT) is important for organ development, metastasis, cancer stemness, and organ fibrosis. Molecular mechanisms to coordinately regulate hypoxia-induced EMT remain elusive. Here, we show that HIF-1α-induced histone deacetylase 3 (hdac3) is essential for hypoxia-induced EMT and metastatic phenotypes. Change of specific chromatin states is associated with hypoxia-induced EMT. Under hypoxia, HDAC3 interacts with hypoxia-induced WDR5, recruits the histone methyltransferase (HMT) complex to increase histone H3 lysine 4 (H3K4)-specific HMT activity, and activates mesenchymal gene expression. HDAC3 also serves as an essential corepressor to repress epithelial gene expression. Knockdown of WDR5 abolishes mesenchymal gene activation but not epithelial gene repression during hypoxia. These results indicate that hypoxia induces different chromatin modifiers to coordinately regulate EMT through distinct mechanisms.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (117 K)Download as PowerPoint slideHighlights► Activation of HDAC3 by HIF-1α is required for hypoxia-induced EMT and metastasis ► Change of chromatin states is associated with hypoxia-induced EMT ► HDAC3 recruits hypoxia-induced WDR5 to increase histone methyltransferase activity ► Hypoxia coordinately regulates EMT through distinct mechanisms