RGS6 suppresses TGF-β-induced epithelial–mesenchymal transition in non-small cell lung cancers via a novel mechanism dependent on its interaction with SMAD4

Regulator of G-protein signaling 6 (RGS6) is a newly discovered tumor suppressor that has been shown to be protective in development of various cancers such as breast cancer and bladder cancer. But the mechanisms underlying these tumor-suppressing functions of RGS6 are not fully understood. Here, we discover a novel function of RGS6 in suppressing TGF-β-induced epithelial–mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC) cells and in vivo NSCLC metastasis. Using both bioinformatics and experimental tools, we showed that RGS6 was downregulated in lung cancer tissues compared to noncancerous counterparts, and low expression of RGS6 was associated with poor survival of lung cancer patients. Overexpression of RGS6 suppressed TGF-β-induced EMT in vitro and TGF-β-promoted metastasis in vivo, by impairing gene expression of downstream effectors induced by the canonical TGF-β-SMAD signaling. The ability of RGS6 to suppress TGF-β-SMAD-mediated gene expression relied on its binding to SMAD4 to prevent complex formation between SMAD4 and SMAD2/3, but independent of its regulation of the G-protein signaling. Interaction between RGS6 and SMAD4 caused less nuclear entry of p-SMAD3 and SMAD4, resulting in inefficient SMAD3-mediated gene expression. Taken together, our findings reveal a novel and noncanonical role of RGS6 in regulation of TGF-β-induced EMT and metastasis of NSCLC and identify RGS6 as a prognostic marker and a potential novel target for NSCLC therapy.