The histone methyltransferase WHSC1 is regulated by EZH2 and is important for ovarian clear cell carcinoma cell proliferation

BMC Cancer

Kazunori Nagasaka¹  Kayo Asada²  Osamu Wada-Hiraike²  Shinya Oki²  Hidenori Machino²  Yoko Matsumoto²  Mayuyo Mori-Uchino²  Machiko Kojima²  Katsutoshi Oda²  Yoshiko Kawata²  Kenbun Sone²  Yutaka Osuga²  Asako Kukita²  Tetsushi Tsuruga²  Harunori Honjoh²  Tomoko Kashiyama²  Tomoyuki Fujii²  Michihiro Tanikawa²  Ryuji Hamamoto³  Syuzo Kaneko³ 

[1] 0000 0000 9239 9995, grid.264706.1, Department of Obstetrics and Gynecology, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, 173 0003, Tokyo, Japan;0000 0001 2151 536X, grid.26999.3d, Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, 113-8655, Tokyo, Japan;0000 0001 2168 5385, grid.272242.3, Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, 104-0045, Tokyo, Japan;

关键词: Histone methyltransferase, Wolf-Hirschhorn syndrome candidate gene-1;    Enhancer of zeste homolog 2;    Ovarian clear cell carcinoma;    Epigenetic modifier;    EZH2 selective inhibitor, H3K36 dimethylation, cell proliferation;   

DOI  :  10.1186/s12885-019-5638-9

来源: publisher

【 摘 要 】

BackgroundWolf-Hirschhorn syndrome candidate gene-1 (WHSC1), a histone methyltransferase, has been found to be upregulated and its expression to be correlated with expression of enhancer of zeste homolog 2 (EZH2) in several cancers. In this study, we evaluated the role of WHSC1 and its therapeutic significance in ovarian clear cell carcinoma (OCCC).MethodsFirst, we analyzed WHSC1 expression by quantitative PCR and immunohistochemistry using 23 clinical OCCC specimens. Second, the involvement of WHSC1 in OCCC cell proliferation was evaluated by MTT assays after siRNA-mediated WHSC1 knockdown. We also performed flow cytometry (FACS) to address the effect of WHSC1 on cell cycle. To examine the functional relationship between EZH2 and WHSC1, we knocked down EZH2 using siRNAs and checked the expression levels of WHSC1 and its histone mark H3K36m2 in OCCC cell lines. Finally, we checked WHSC1 expression after treatment with the selective inhibitor, GSK126.ResultsBoth quantitative PCR and immunohistochemical analysis revealed that WHSC1 was significantly overexpressed in OCCC tissues compared with that in normal ovarian tissues. MTT assay revealed that knockdown of WHSC1 suppressed cell proliferation, and H3K36me2 levels were found to be decreased in immunoblotting. FACS revealed that WHSC1 knockdown affected the cell cycle. We also confirmed that WHSC1 expression was suppressed by EZH2 knockdown or inhibition, indicating that EZH2 is upstream of WHSC1 in OCCC cells.ConclusionsWHSC1 overexpression induced cell growth and its expression is, at least in part, regulated by EZH2. Further functional analysis will reveal whether WHSC1 is a promising therapeutic target for OCCC.

【 授权许可】

CC BY