title: EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.
abstract: EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2'-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ihira
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
authors.forename: Peixin
authors.initials: P
authors.lastname: Dong
authors.affiliation: Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
authors.forename: Hidemichi
authors.initials: H
authors.lastname: Watari
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Konno
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
authors.forename: Sharon J B
authors.initials: SJ
authors.lastname: Hanley
authors.affiliation: Division of Cancer Biology, Institute for Genetic Medicine Hokkaido University N15, W7, Sapporo 0608638, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Noguchi
authors.affiliation: Division of Cancer Biology, Institute for Genetic Medicine Hokkaido University N15, W7, Sapporo 0608638, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hirata
authors.affiliation: Division of Cancer Biology, Institute for Genetic Medicine Hokkaido University N15, W7, Sapporo 0608638, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Suizu
authors.affiliation: Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kudo
authors.affiliation: Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.|Department of Women's Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sakuragi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; C586265:GSK343; D007191:Indazoles; C575475:MIRN361 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011728:Pyridones; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: 5-AZA-CdR; EZH2; GSK343; endometrial cancer; miR-361