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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

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

Murai Fumihiko F Koinuma Daizo D Shinozaki-Ushiku Aya A Fukayama Masashi M Miyaozono Kohei K Ehata Shogo S

Cell discovery 20150922

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 sma ...[more]

PMID: 27462425

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Project description:BackgroundLung cancer has the highest case fatality rate among cancers because of uncontrolled proliferation and early metastasis of cancer cells in the lung tissue. This study aimed to clarify the role of the non-SMC condensin I complex, subunit G (NCAPG) in lung adenocarcinoma (LUAD), explore the mechanisms of its progression, and lay the foundation for the search for new biological markers.MethodsWe analyzed overlapping differentially expressed genes (DEGs) from three datasets; a protein-protein interaction (PPI) network was subsequently constructed and analyzed using Cytoscape. We then selected NCAPG for validation because of its poor prognosis and because it has not been sufficiently studied in the context of LUAD. Immunohistochemical analysis was used to detect the expression of NCAPG in LUAD tissues, and the relationships between NCAPG and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to verify the role of NCAPG in LUAD. Finally, we studied the specific mechanism of action of NCAPG in LUAD.ResultsThrough comprehensive analysis of the GSE43458, GSE75037, and The Cancer Genome Atlas databases, we identified 517 overlapping DEGs. Among them, NCAPG was identified as a hub gene. Immunohistochemical analysis revealed that NCAPG was strongly associated with the clinical stage, M-classification, and N-classification. Univariate and multivariate Cox regression analyses indicated that NCAPG was a prognostic risk factor for LUAD, while the in vitro experiments showed that NCAPG overexpression promoted proliferation, migration, invasion, and epithelial-mesenchymal transition. Furthermore, knockdown of NCAPG inhibited LUAD progression, both in vitro and in vivo. Mechanistically, NCAPG overexpression increased p-Smad2 and p-Smad3 expressions in the transforming growth factor β (TGF-β) signaling pathway. Additionally, rescue experiments indicated that TGF-β signaling pathway inhibitors could restore the effect of NCAPG overexpression in LUAD cells.ConclusionsNCAPG may promote proliferation and migration via the TGF-β signaling pathway in LUAD.

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

Publications

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

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