NHERF1, a novel GPER associated protein, increases stability and activation of GPER in ER-positive breast cancer.
NHERF1, a novel GPER associated protein, increases stability and activation of GPER in ER-positive breast cancer.
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NHERF1 是一种新型 GPER 相关蛋白，可增加 ER 阳性乳腺癌中 GPER 的稳定性和活化
DOI：
10.18632/oncotarget.10713
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发表时间：
2016-08-23
期刊：
影响因子：
--
通讯作者：
He J
中科院分区：
文献类型：
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作者：
Meng R;Qin Q;Xiong Y;Wang Y;Zheng J;Zhao Y;Tao T;Wang Q;Liu H;Wang S;Jiang WG;He J
G蛋白偶联的雌激素受体（GPER）在介导雌二醇的作用中起重要作用。高水平的GPE与侵入性乳腺癌（IBC）的恶性进展有关。但是，调节GPER蛋白水平的机制尚不清楚。在这项研究中，发现PDZ蛋白Na+/H+交换器调节因子（NHERF1）与乳腺癌细胞中的GPE相互作用。这种相互作用是由NHERF1的PDZ2结构域和GPER的羧基末端PDZ结合基序介导的。证明了NHERF1可以在转录后水平上促进GPER表达，并通过以GPER/NHERF1相互作用依赖性方式通过泛素蛋白蛋白酶体途径抑制受体降解，从而提高GPER蛋白稳定性。此外，GPER蛋白水平与雌激素受体（ER）阳性乳腺癌细胞的NHERF1蛋白水平呈正相关。此外，对来自癌症基因组图集（TCGA）的临床IBC数据的分析显示，ER阳性IBC和正常乳腺组织之间的GPER mRNA水平无显着差异。然而，基因集富集分析（GSEA）表明，与正常相比，GPER信号在ER阳性IBC中被超激活，并且其激活与NHERF1 mRNA水平呈正相关。综上所述，我们的发现将NHERF1确定为GPER的新结合伴侣，其过表达促进了ER阳性IBC中GPER的蛋白质稳定性和激活。我们的数据表明，NHERF1对GPER的稳定性调节可能有助于GPER介导的ER阳性IBC的致癌作用。
G protein-coupled estrogen receptor (GPER) plays an important role in mediating the effects of estradiol. High levels of GPER have been implicated to associate with the malignant progress of invasive breast cancer (IBC). However, the mechanisms by which GPER protein levels were regulated remain unclear. In this study, PDZ protein Na+/H+ exchanger regulatory factor (NHERF1) was found to interact with GPER in breast cancer cells. This interaction was mediated by the PDZ2 domain of NHERF1 and the carboxyl terminal PDZ binding motif of GPER. NHERF1 was demonstrated to facilitate GPER expression at post-transcriptional level and improve GPER protein stability by inhibiting the receptor degradation via ubiquitin-proteasome pathway in a GPER/NHERF1 interaction-dependent manner. In addition, GPER protein levels are positively associated with NHERF1 protein levels in a panel of estrogen receptor (ER)-positive breast cancer cells. Furthermore, analysis of clinical IBC data from The Cancer Genome Atlas (TCGA) showed no significant difference in GPER mRNA levels between ER-positive IBC and normal breast tissues. However, gene set enrichment analysis (GSEA) showed that GPER signaling is ultra-activated in ER-positive IBC when compared with normal and its activation is positively associated with NHERF1 mRNA levels. Taken together, our findings identify NHERF1 as a new binding partner for GPER and its overexpression promotes protein stability and activation of GPER in ER-positive IBC. Our data indicate that regulation of GPER stability by NHERF1 may contribute to GPER-mediated carcinogenesis in ER-positive IBC.