Repression of TIFγ by SOX2 promotes TGF-β-induced epithelial-mesenchymal transition in non-small-cell lung cancer

TIF1 gamma is a novel regulator of transforming growth factor (TGF)-beta/Smad signaling. Our previous studies show that dysregulated expression of transcriptional intermediary factor 1 gamma (TIF1 gamma) and abnormal TGF-beta/Smad signaling are implicated in non-small-cell lung cancer (NSCLC) separately. However, how TIF1 gamma contributes to NSCLC by controlling TGF-beta/Smad signaling is poorly understood. Here, we investigated the mechanistic role of TIF1 gamma in TGF-beta-induced epithelial-mesenchymal transition (EMT), as well as a link between TIF1 gamma and SOX2 in NSCLC. We show that TIF1 gamma is a downstream target of SOX2 in NSCLC cells. SOX2 overexpression negatively regulated TIF1 gamma promoter activity and thereby attenuated TIF1 gamma mRNA and protein expression levels; SOX2 knockdown significantly enhanced TIF1 gamma promoter activity and augmented TIF1 gamma expression. Moreover, TIF1 gamma mRNA expression was downregulated in human NSCLC tissues and negatively correlated with SOX2 protein, which was upregulated in NSCLC tissues. Importantly, knockdown of TIF1 gamma or SOX2 overexpression augmented SMAD4 (human Mad (mothers against decapentaplegic)-related homologous protein 4)-dependent transcriptional responses, and enhanced TGF-beta-induced EMT and human NSCLC cell invasion; knockdown of SOX2 impaired TGF-beta-induced EMT and NSCLC cell invasion. In an in vivo model of metastasis, knockdown of TIF1 gamma promotes NSCLC cell metastasis. In addition, our data suggested that TIF1 gamma inhibited TGF-beta-induced EMT through competing with SMAD4 in NSCLC cells. Taken together, our findings reveal a new mechanism by which SOX2-mediated transcription repression of TIF1 gamma promotes TGF-beta-induced EMT in NSCLC.