Opposing Effects of KLF5 on the Transcription of MYC in Epithelial Proliferation in the Context of Transforming Growth Factor β

The proto-oncogene MYC plays a critical role in cell proliferation and tumorigenesis, and its down-regulation by transforming growth factor beta (TGF beta) signaling is necessary for TGF beta to inhibit cell proliferation. KLF5, on the other hand, is a pro-proliferative basic transcription factor that reverses function to become an anti-proliferative TGF beta cofactor upon TGF beta stimulation in epithelial homeostasis. In this study we investigated whether KLF5 directly regulates MYC transcription in epithelial cells in the context of TGF beta Knockdown of KLF5 significantly reduced MYC expression in the HaCaT epidermal epithelial cells. When TGF beta was applied, however, whereas MYC expression was significantly inhibited, knockdown of KLF5 increased MYC expression. Furthermore, re-expression of KLF5 restored the inhibitory effect of TGF beta on MYC expression in two cancer cell lines. Chromatin immunoprecipitation and oligo pulldown experiments demonstrated that whereas binding of KLF5 to both KLF5 binding element (KBE) and TGF beta inhibitory element (TIE) DNA elements was necessary for MYC transcription, binding to KBE was decreased by TGF beta and binding to TIE was increased by TGF beta These results suggest that KLF5 is not only essential for MYC transcription in proliferating epithelial cells but also mediates the inhibitory effect of TGF beta on MYC transcription. Furthermore, different binding sites mediate different effects of KLF5 in the context of TGF beta.