Ski regulates Smads and TAZ signaling to suppress lung cancer progression.

Ski, the transforming protein of the avian Sloan-Kettering retrovirus, displays both pro- and anti-oncogenic activities in human cancer. The mechanisms underlying these conflicting observations have not been fully understood. Herein, we investigated the mechanism underlying the tumor suppressor activity of Ski. To investigate the effect of Ski re-activation on TGF-ß and Hippo/TAZ pathway, we measured its effect on the endogenous Smad target genes (PAI-1 and P15INK4B ) and TAZ target gene CTGF. The results revealed that Ski exerted its inhibitory activity in TGF-ß1/Smad signaling pathway. Ski inhibited TAZ by increasing their phosphorylation by Lats2 and did not alter the localization of TAZ. Ski inhibited lung cancer growth and invasion. Ski methylation correlated with decreased mRNA expression in human lung cancer cell lines. Thus, Ski inhibited the function of TGF-ß and TAZ through multiple mechanisms in human lung cancer.