The Feedback Regulation Of IDH1 On TGF-? Signalling

Transforming growth factor ?(TGF-?)induces the activation of fibroblasts and promotes epithelial-mesenchymal transition(EMT)of tumour cells.TGF-? signalling also regulates the expression of enzymes involved in cell metabolism.In our preliminary study,isocitrate dehydrogenase 1(IDH1)was down-regulated by TGF-?/Smad signalling.But whether IDH1 affects TGF-? signalling is unknown.In this study,we found that TGF-? signalling directly regulated IDH1 expression,and IDH1 feedback regulated TGF-? signalling.The canonical TGF-?/Smad signalling down-regulated IDH1 expression.Activated TGFBR was finally internalized by the caveola comprising of Cav1,whose expression was modulated by the levels of H3K4/H3K9 methylation on its promoter.Our data showed that the transcription of Cav1 decreased when ?-KG concentration increased since the ?-KG was an allosteric regulator of histone methyltransferase.Downregulation of Cav1 postponed the internalization of TGF-? receptor on cell membrane.With TGF-?1 stimulation,IDH1 downregulation enhanced TGF-?/Smad signalling while IDH1 overexpression weakened TGF-? signal,including TGFBR-dependent p38 and Erk signalling.Moreover,IDH1 also affected the biological function of TGF-? signalling.The downregulation of IDH1 in fibroblasts promoted A375 proliferation and accelerated xenograft tumor growth.In breast cancer,IDH1 downregulation promoted EMT;in contrast,IDH1 overexpression attenuated TGF-?1-induced EMT.In brief,this study demonstrated that canonical TGF-?/Smad signalling regulates the expression of metabolic enzyme IDH1;in turn,TGFBR-IDH1-Cav1 signalling promotes canonical TGF-?/Smad signalling,enhances fibroblasts activation and cancer cells epithelial-mesenchymal transition.