Murai Fumihiko, Koinuma Daizo, Shinozaki-Ushiku Aya, Fukayama Masashi, Miyaozono Kohei, Ehata Shogo
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.
Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.
Cell Discov. 2015 Sep 22;1:15026. doi: 10.1038/celldisc.2015.26. eCollection 2015.
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.
转化生长因子-β（TGF-β）可诱导多种癌细胞凋亡，发挥肿瘤抑制作用。我们对TGF-β信号传导进行了功能分析，以确定调节小细胞肺癌细胞生存的分子机制。在此，我们发现与正常肺上皮细胞和正常肺组织相比，大多数小细胞肺癌细胞和组织中TGF-β II型受体（TβRII）表达较低。当野生型TβRII在小细胞肺癌细胞中过表达时，TGF-β通过诱导凋亡在体外抑制细胞生长，在体内抑制肿瘤形成。包括zeste 2增强子（EZH2）在内的多梳抑制复合物2的成分在小细胞肺癌细胞中高表达；这导致TβRII表达的表观遗传沉默以及TGF-β介导的凋亡抑制。Achaete-scute家族bHLH转录因子1（ASCL1；也称为ASH1）是TGF-β的Smad依赖性靶点，被发现可诱导小细胞肺癌细胞的生存。因此，EZH2通过抑制TGF-β-Smad-ASCL1途径促进小细胞肺癌进展。
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