Dlx-2 is implicated in TGF-β- and Wnt-induced epithelial-mesenchymal, glycolytic switch, and mitochondrial repression by Snail activation.

Epithelial-mesenchymal transition (EMT) and oncogenic metabolism (including glycolytic switch) are important for tumor development and progression. Here, we show that Dlx-2, one of distal-less (Dlx) homeobox genes, induces EMT and glycolytic switch by activation of Snail. In addition, it was induced by TGF-β and Wnt and regulates TGF-β- and Wnt-induced EMT and glycolytic switch by activating Snail. We also found that TGF-β/Wnt suppressed cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, in a Dlx-2/Snail-dependent manner. TGF-β/Wnt appeared to downregulate the expression of various COX subunits including COXVIc, COXVIIa and COXVIIc; among these COX subunits, COXVIc was a common target of TGF-β, Wnt, Dlx-2 and Snail, indicating that COXVIc downregulation plays an important role(s) in TGF-β/Wnt-induced COX inhibition. Taken together, our results showed that Dlx-2 is involved in TGF-β- and Wnt-induced EMT, glycolytic switch, and mitochondrial repression by Snail activation.