Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells

Takashina, Taichi; Kinoshita, Ichiro; Kikuchi, Junko; Shimizu, Yasushi; Sakakibara-Konishi, Jun; Oizumi, Satoshi; Nishimura, Masaharu; Dosaka-Akita, Hirotoshi

Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells

Takashina, Taichi; Kinoshita, Ichiro; Kikuchi, Junko et al.

Cancer science, 2016, 107(7), 955-962

Permalink : https://hdl.handle.net/2115/63792

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アクセス権	open access
URI	https://hdl.handle.net/2115/63792
タイトル	Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells
著者	Takashina, Taichi ; Kinoshita, Ichiro ; Kikuchi, Junko ; Shimizu, Yasushi ; Sakakibara-Konishi, Jun ; Oizumi, Satoshi ; Nishimura, Masaharu ; Dosaka-Akita, Hirotoshi
著者名 Takashina, Taichi
e-Rad_Researcher 40343008 著者名 Kinoshita, Ichiro
著者名 Kikuchi, Junko
e-Rad_Researcher 10374513 著者名 Shimizu, Yasushi
e-Rad_Researcher 50374278 著者名 Sakakibara-Konishi, Jun
e-Rad_Researcher 10421968 著者名 Oizumi, Satoshi
e-Rad_Researcher 00208224 著者名 Nishimura, Masaharu
e-Rad_Researcher 70222528 著者名 Dosaka-Akita, Hirotoshi
言語	英語
キーワード	3-Deazaneplanocin A
	EZH2
	lung cancer
	polycomb-group protein
	vorinostat (suberoylanilide hydroxamic acid)
発行日	2016-07
出版者	Wiley-Blackwell
収録物名	Cancer science
巻(号)	107(7)
ページ	955-962
抄録	Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non-small-cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3-deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co-treatment with 3-deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co-treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co-treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co-treatment strongly suppressed EGFR signaling, not only in EGFR-wild-type NSCLC cells, but also in EGFR-mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co-treatment suppressed the in vivo tumor growth of EGFR-mutant, EGFR-tyrosine kinase-resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC.
資源タイプ	学術雑誌論文
出版タイプ	Version of Record
権利情報	Creative Commons Attribution-NonCommercial 4.0 International
PISSN	1347-9032
関連情報 (isIdenticalTo)	出版社版DOI https://doi.org/10.1111/cas.12957