Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells.
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.
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Taichi
T
Takashina
Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Ichiro
I
Kinoshita
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Junko
J
Kikuchi
Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Yasushi
Y
Shimizu
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Jun
J
Sakakibara-Konishi
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Satoshi
S
Oizumi
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Masaharu
M
Nishimura
Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Hirotoshi
H
Dosaka-Akita
D000107:Acetylation / Q000187:drug effects; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019925:Cyclin A / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004357:Drug Synergism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000172:deficiency; D044127:Epigenesis, Genetic / Q000187:drug effects*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D019925:Cyclin A; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D050760:Cyclin-Dependent Kinase Inhibitor p27; C048460:3-deazaneplanocin; D000077337:Vorinostat; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C512478:EGFR protein, human; D066246:ErbB Receptors; D006655:Histone Deacetylases; D000241:Adenosine
3-Deazaneplanocin A; EZH2; lung cancer; polycomb-group protein; vorinostat (suberoylanilide hydroxamic acid)