A positive role for Myc in TGFβ-induced Snail transcription and epithelial-to-mesenchymal transition

Myc and transforming growth factor-beta (TGF beta) signaling are mutually antagonistic, that is Myc suppresses the activation of TGF beta-induced genes, whereas TGF beta represses c-myc transcription. Here, we report a positive role for Myc in the TGF beta response, consisting in the induction of an epithelial-to-mesenchymal transition (EMT) and the activation of the EMT-associated gene Snail. Knockdown of either Myc or the TGF beta effectors SMAD3/4 in epithelial cells eliminated Snail induction by TGF beta. Both Myc and SMAD complexes targeted the Snail promoter in vivo, DNA binding occurring in a mutually independent manner. Myc was bound prior to TGF beta treatment, and was required for rapid Snail activation upon SMAD binding induced by TGF beta. On the other hand, c-myc downregulation by TGF beta was a slower event, occurring after Snail induction. The response of Snail to another cytokine, hepatocyte growth factor (HGF), also depended on Myc and SMAD4. Thus, contrary to their antagonistic effects on Cip1 and INK4b, Myc and SMADs cooperate in signal-dependent activation of Snail in epithelial cells. Although Myc also targeted the Snail promoter in serum-stimulated fibroblasts, it was dispensable for its activation in these conditions, further illustrating that the action of Myc in transcriptional regulation is context-dependent. Our findings suggest that Myc and TGF beta signaling may cooperate in promoting EMT and metastasis in carcinomas.