SWI/SNF Antagonism of PRC2 Mediates Estrogen-Induced Progesterone Receptor Expression.
SWI/SNF Antagonism of PRC2 Mediates Estrogen-Induced Progesterone Receptor Expression.
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DOI：
10.3390/cells11061000
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发表时间：
2022-03-15
期刊：
影响因子：
6
通讯作者：
Chandler RL
中科院分区：
文献类型：
--
作者：
Wilson MR;Reske JJ;Koeman J;Adams M;Joshi NR;Fazleabas AT;Chandler RL
子宫内膜癌（EC）的特点是雌激素水平高，黄体酮不对抗。孕激素治疗是早期EC的标准，但对孕激素的反应取决于孕激素受体（PGR）的表达。在这里，我们发现子宫内膜上皮细胞中PGR的表达依赖于ARID1A， ARID1A是SWI/SNF染色质重塑复合体的dna结合亚基，在EC中通常发生突变。在雌激素受体过表达的子宫内膜上皮细胞中，我们发现ARID1A促进雌激素信号传导并调节常见的基因表达程序。正常情况下，表达雌激素受体的子宫内膜上皮细胞通过上调PGR来响应雌激素。然而，当ARID1A表达缺失时，PGR表达上调明显降低。这种现象也可能发生在SWI/SNF亚基BRG1缺失之后，这表明含有ARID1A和BRG1的复合物在PGR调控中起作用。我们发现PGR受二价启动子调控，该启动子包含H3K4me3和H3K27me3组蛋白尾部修饰。H3K27me3由EZH2沉积，在ARID1A缺失的情况下，EZH2的抑制导致雌激素诱导的PGR表达的恢复。我们的研究结果表明ARID1A缺陷在晚期EC中PGR的丢失中起作用，并且EZH2抑制剂在这种疾病中具有治疗效用。
Endometrial cancer (EC) is characterized by high estrogen levels unopposed by progesterone. Treatment with progestins is standard for early EC, but the response to progestins is dependent on progesterone receptor (PGR) expression. Here, we show that the expression of PGR in endometrial epithelial cells is dependent on ARID1A, a DNA-binding subunit of the SWI/SNF chromatin-remodeling complex that is commonly mutated in EC. In endometrial epithelial cells with estrogen receptor overexpression, we find that ARID1A promotes estrogen signaling and regulates common gene expression programs. Normally, endometrial epithelial cells expressing estrogen receptors respond to estrogen by upregulating the PGR. However, when ARID1A expression is lost, upregulation of PGR expression is significantly reduced. This phenomenon can also occur following the loss of the SWI/SNF subunit BRG1, suggesting a role for ARID1A- and BRG1-containing complexes in PGR regulation. We find that PGR is regulated by a bivalent promoter, which harbors both H3K4me3 and H3K27me3 histone tail modifications. H3K27me3 is deposited by EZH2, and inhibition of EZH2 in the context of ARID1A loss results in restoration of estrogen-induced PGR expression. Our results suggest a role for ARID1A deficiency in the loss of PGR in late-stage EC and a therapeutic utility for EZH2 inhibitors in this disease.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
DOI：
10.1097/igc.0b013e318296a265
发表时间：
2013-07
期刊：
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
影响因子：
--
作者：
Eskander RN;Ji T;Huynh B;Wardeh R;Randall LM;Hoang B
通讯作者：
Hoang B
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Franco, Heather L.;Rubel, Cory A.;DeMayo, Francesco J.
通讯作者：
DeMayo, Francesco J.