SIRT1 inactivation evokes antitumor activities in NSCLC through the tumor suppressor p27.

UNLABELLED: P27(Kip1) (CDKN1B) regulates cellular proliferation and senescence, and p27(Kip1) deficiency in cancer is strongly correlated with poor prognosis of multiple cancer types. Understanding the mechanism of p27(Kip1) loss in cancer and the consequences of restoring p27(Kip1) levels is therefore critical for effective management during therapy. Here, SIRT1, a class III histone deacetylase (HDAC), is identified as an important regulator of p27(Kip1) expression. Mechanistically, SIRT1 reduces p27(Kip1) expression by decreasing p27(Kip1) protein stability through the ubiquitin-proteasome pathway. In addition, SIRT1 silencing suppresses non-small cell lung cancer (NSCLC) proliferation and induces senescence in a p27(Kip1)-dependent manner. Furthermore, SIRT1 silencing dramatically suppresses tumor formation and proliferation in two distinct NSCLC xenograft mouse models. Collectively, these data demonstrate that not only SIRT1 is an important regulator of p27(Kip1) but also SIRT inhibition induces senescence and antigrowth potential in lung cancer in vivo. IMPLICATIONS: SIRT1 is a key regulator of p27 protein levels and SIRT1 inhibition is a viable strategy for NSCLC therapy by means of p27 reactivation. ©2014 American Association for Cancer Research.