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

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Title: Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells
Authors: Takashina, Taichi Browse this author
Kinoshita, Ichiro Browse this author →KAKEN DB
Kikuchi, Junko Browse this author
Shimizu, Yasushi Browse this author →KAKEN DB
Sakakibara-Konishi, Jun Browse this author →KAKEN DB
Oizumi, Satoshi Browse this author →KAKEN DB
Nishimura, Masaharu Browse this author →KAKEN DB
Dosaka-Akita, Hirotoshi Browse this author →KAKEN DB
Keywords: 3-Deazaneplanocin A
lung cancer
polycomb-group protein
vorinostat (suberoylanilide hydroxamic acid)
Issue Date: Jul-2016
Publisher: Wiley-Blackwell
Journal Title: Cancer science
Volume: 107
Issue: 7
Start Page: 955
End Page: 962
Publisher DOI: 10.1111/cas.12957
Abstract: 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.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 木下 一郎

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