LSD1 sustains estrogen-driven endometrial carcinoma cell proliferation through the PI3K/AKT pathway via di-demethylating H3K9 of cyclin D1
LSD1 sustains estrogen-driven endometrial carcinoma cell proliferation through the PI3K/AKT pathway via di-demethylating H3K9 of cyclin D1
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LSD1 通过使细胞周期蛋白 D1 的 H3K9 二去甲基化，通过 PI3K/AKT 途径维持雌激素驱动的子宫内膜癌细胞增殖
DOI：
10.3892/ijo.2017.3849
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发表时间：
2017-03-01
影响因子：
5.2
通讯作者：
Wu, Sufang
中科院分区：
文献类型：
--
作者：
Chen, Chunqin;Wang, Yanan;Wu, Sufang
最近的研究报道组蛋白赖氨酸特异性去甲基化酶1（LSD 1，KDM 1A）在子宫内膜样癌（EEC）中过表达，并与肿瘤进展和不良预后相关。然而，LSD 1在子宫内膜癌（EC）中的生理功能和机制仍不清楚。在这项研究中，我们证明，β-雌二醇（E2）治疗增加LSD 1表达通过GPR 30/PI 3 K/AKT途径在子宫内膜癌细胞。siGPR 30和PI 3 K抑制剂LY 294002都阻断了这种作用。RNAi介导的LSD 1沉默可抑制雌激素诱导的子宫内膜癌细胞（ECC）增殖，并诱导G1期细胞阻滞和凋亡。从机制上讲，我们发现LSD 1沉默导致PI 3 K/AKT信号失活，但没有预期的PTEN表达升高。这是因为LSD 1的抑制诱导赖氨酸9在细胞周期蛋白D1的启动子区对组蛋白H3（H3 K9 m2）积累的二甲基化。干扰细胞周期蛋白D1导致PI 3 K/AKT信号抑制。LSD 1敲低的ECC中细胞周期蛋白D1的再过表达逆转了LSD 1抑制作用。我们的发现将雌激素信号传导与EEC中的表观遗传调控联系起来，并为LSD 1作为子宫内膜癌治疗的潜在靶点提供了新的实验支持。
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.