EZH2 promotes progression of small cell lung cancer by suppressing the TGF-?-Smad-ASCL1 pathway.

ABSTRACT: Transforming growth factor-? (TGF-?) induces apoptosis in many types of cancer cells and acts as a tumor suppressor. We performed a functional analysis of TGF-? signaling to identify a molecular mechanism that regulated survival in small cell lung cancer cells. Here, we found low expression of TGF-? type II receptor (T?RII) in most small cell lung cancer cells and tissues compared to normal lung epithelial cells and normal lung tissues, respectively. When wild-type T?RII was overexpressed in small cell lung cancer cells, TGF-? suppressed cell growth in vitro and tumor formation in vivo through induction of apoptosis. Components of polycomb repressive complex 2, including enhancer of zeste 2 (EZH2), were highly expressed in small cell lung cancer cells; this led to epigenetic silencing of T?RII expression and suppression of TGF-?-mediated apoptosis. Achaete-scute family bHLH transcription factor 1 (ASCL1; also known as ASH1), a Smad-dependent target of TGF-?, was found to induce survival in small cell lung cancer cells. Thus, EZH2 promoted small cell lung cancer progression by suppressing the TGF-?-Smad-ASCL1 pathway.

SUBMITTER: Murai F 

PROVIDER: S-EPMC4860843 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature