期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 50, 期 3, 页码 942-952出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2017.3849
关键词
LSD1; cyclin D1; endometrial cancer; PI3K/AKT; PTEN; estrogen
类别
资金
- National Key Clinical Specialist Construction Programs of China
- National Natural Science Foundation of China [81201541, 81502230, 81402134]
- Shanghai Pu Jiang Talent Program [12PJDO02]
A recent study reported that histone lysine specific demethylase 1 (LSD1, KDM1A) is overexpressed in endometrioid endometrial carcinoma (EEC) and associated with tumor progression as well as poor prognosis. However, the physiological function and mechanism of LSD1 in endometrial cancer (EC) remains largely unknown. In this study, we demonstrate that (beta-estradiol (E2) treatment increased LSD1 expression via the GPR30/PI3K/AKT pathway in endometrial cancer cells. Both siGPR30 and the PI3K inhibitor LY294002 block this effect. RNAi-mediated silencing of LSD1 abolished estrogen-driven endometrial cancer cell (ECC) proliferation, and induced G1 cell arrest and apoptosis. Mechanistically, we find that LSD1 silencing results in PI3K/AKT signal inactivation, but without the elevation of PTEN expression as expected. This is because the inhibition of LSD1 induces dimethylation of lysine 9 on histone H3 (H3K9m2) accumulation at the promoter region of cyclin Dl. Interfering with cyclin Dl leads to PI3K/AKT signal suppression. Re-overexpression of cyclin Dl in LSD1-knockdown ECCs reverses the LSD1 inhibitory action. Our finding connects estrogen signaling with epigenetic regulation in EEC and provides novel experimental support for LSD1 as a potential target for endometrial cancer therapeutics.
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