
Combined inhibition of EZH 2 and histone deacetylases as a potential epigenetic therapy for non‐small‐cell lung cancer cells
Author(s) -
Takashina Taichi,
Kinoshita Ichiro,
Kikuchi Junko,
Shimizu Yasushi,
SakakibaraKonishi Jun,
Oizumi Satoshi,
Nishimura Masaharu,
DosakaAkita Hirotoshi
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12957
Subject(s) - cancer research , vorinostat , epigenetic therapy , histone h3 , biology , histone deacetylase , epigenetics , cancer epigenetics , cell growth , cancer cell , histone methyltransferase , histone , chemistry , cancer , dna methylation , biochemistry , gene expression , genetics , gene
Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH 2, the catalytic subunit of polycomb repressive complex 2 ( PRC 2), is frequently overexpressed in non‐small‐cell lung cancer ( NSCLC ) and that an EZH 2 inhibitor, 3‐deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH 2 was recently shown to be required for the activity of histone deacetylases ( HDAC s) that interact with another PRC 2 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 EZH 2 and other PRC 2 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 EZH 2 and HDAC s may provide more effective epigenetic therapeutics for NSCLC .