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

Transforming growth factor-beta (TGF-beta) induces apoptosis in many types of cancer cells and acts as a tumor suppressor. We performed a functional analysis of TGF-beta signaling to identify a molecular mechanism that regulated survival in small cell lung cancer cells. Here, we found low expression of TGF-beta type II receptor (T beta 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 beta RII was overexpressed in small cell lung cancer cells, TGF-beta 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 beta RII expression and suppression of TGF-beta mediated apoptosis. Achaete-scute family bHLH transcription factor 1 (ASCL1; also known as ASH1), a Smad-dependent target of TGF-beta, was found to induce survival in small cell lung cancer cells. Thus, EZH2 promoted small cell lung cancer progression by suppressing the TGF-beta-Smad-ASCL1 pathway.