title: EZH2 promotes progression of small cell lung cancer by suppressing the TGF-β-Smad-ASCL1 pathway.
abstract: Transforming growth factor-β (TGF-β) induces apoptosis in many types of cancer cells and acts as a tumor suppressor. We performed a functional analysis of TGF-β signaling to identify a molecular mechanism that regulated survival in small cell lung cancer cells. Here, we found low expression of TGF-β type II receptor (TβRII) in most small cell lung cancer cells and tissues compared to normal lung epithelial cells and normal lung tissues, respectively. When wild-type TβRII was overexpressed in small cell lung cancer cells, TGF-β 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 TβRII expression and suppression of TGF-β-mediated apoptosis. Achaete-scute family bHLH transcription factor 1 (ASCL1; also known as ASH1), a Smad-dependent target of TGF-β, was found to induce survival in small cell lung cancer cells. Thus, EZH2 promoted small cell lung cancer progression by suppressing the TGF-β-Smad-ASCL1 pathway.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Murai
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.
authors.forename: Daizo
authors.initials: D
authors.lastname: Koinuma
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Shinozaki-Ushiku
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyaozono
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ehata
keywords: ASCL1; EZH2; Smad; TGF-β; apoptosis; epigenetics; small cell lung cancer