LSD1 sustains estrogen-driven endometrial carcinoma cell proliferation through the PI3K/AKT pathway via di-demethylating H3K9 of cyclin D1

被引：37

作者：

Chen, Chunqin ^{[1
]}

Wang, Yanan ^{[1
]}

Wang, Shiyu ^{[1
]}

Liu, Yuan ^{[1
]}

Zhang, Jiawen ^{[2
]}

Xu, Yuyao ^{[1
]}

Zhang, Zhenbo ^{[1
]}

Bao, Wei ^{[1
]}

Wu, Sufang ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Obstet & Gynecol, 650 Xinsongjiang Rd, Shanghai 201600, Peoples R China

[2] Shanghai Tongji Univ, Dept Obstet & Gynecol, Shanghai Peoples Hosp 10, Shanghai, Peoples R China

来源：

INTERNATIONAL JOURNAL OF ONCOLOGY | 2017年 / 50卷 / 03期

基金：

中国国家自然科学基金;

关键词：

LSD1; cyclin D1; endometrial cancer; PI3K/AKT; PTEN; estrogen; THERAPEUTIC TARGET; TUMOR PROGRESSION; CANCER; OVEREXPRESSION; ACTIVATION; INHIBITORS; EXPRESSION; MIGRATION; PROGNOSIS; PREDICTS;

D O I：

10.3892/ijo.2017.3849

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：942 / 952

页数：11

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