Differential Regulation of Estrogen Receptor a Expression in Breast Cancer Cells by Metastasis-Associated Protein 1
Differential Regulation of Estrogen Receptor a Expression in Breast Cancer Cells by Metastasis-Associated Protein 1
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DOI：
10.1158/0008-5472.can-13-2020
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发表时间：
2014-03-01
期刊：
影响因子：
11.2
通讯作者：
Lee, Mi-Ock
中科院分区：
文献类型：
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作者：
Kang, Hyun-Jin;Lee, Min-Ho;Lee, Mi-Ock
转移相关蛋白1(MTA1)是核小体重构和组蛋白脱乙酰酶(HDAC)复合体的组成部分，在乳腺癌的发生发展中起重要作用。尽管MTA1被认为是雌激素受体α(ERα)反式激活功能的抑制因子，但它在ERα基因ESR1转录的表观遗传调控中的作用尚未被研究。在这里，我们发现沉默MTA1降低了ERα阳性细胞中ERα的表达水平，但增加了ERα阴性细胞中ERα的表达水平。在MCF7和MDA-MB-231中，MTA1都被招募到ESR1(ERpro315)转录起始点下游+146至+461bp的区域。对编码ERpro315的寡核苷酸拖拽的MTA1复合体的蛋白质组学分析表明，转录因子AP-2γ(Tfap2c)和干扰素-γ诱导蛋白16(IFI16)是该复合体的组成部分。有趣的是，在MCF7中，Tfap2c激活了编码ERpro315的报告基因和ERαmRNA的水平。相反，在MDA-MB-231中，IFI16抑制启动子活性，沉默MTA1增加ERα的表达。重要的是，II类HDAC参与了MTA1介导的ERα的差异性调节。最后，在体外和体内实验中，稳定表达shIFI16或shMTA1的MDA-MB-231来源的细胞系对他莫昔芬诱导的生长抑制更敏感。综上所述，我们的发现提示MTA1-Tfap2c或MTA1-IFI16复合体可能参与乳腺癌ESR1表达的表观遗传调节，并可能决定乳腺癌患者肿瘤对他莫昔芬治疗的敏感性。(C)2014年AACR。
Metastasis-associated protein 1 (MTA1) is a component of the nucleosome remodeling and histone deacetylase (HDAC) complex, which plays an important role in progression of breast cancer. Although MTA1 is known as a repressor of the transactivation function of estrogen receptor alpha (ER alpha), its involvement in the epigenetic control of transcription of the ER alpha gene ESR1 has not been studied. Here, we show that silencing of MTA1 reduced the level of expression of ER alpha in ER alpha-positive cells but increased it in ER alpha-negative cells. In both MCF7 and MDA-MB-231, MTA1 was recruited to the region + 146 to + 461 bp downstream of the transcription start site of ESR1 (ERpro315). Proteomics analysis of the MTA1 complex that was pulled down by an oligonucleotide encoding ERpro315 revealed that the transcription factor AP-2 gamma (TFAP2C) and the IFN-gamma-inducible protein 16 (IFI16) were components of the complex. Interestingly, in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ER alpha mRNA. By contrast, in MDA-MB-231, IFI16 repressed the promoter activity and silencing of MTA1 increased expression of ER alpha. Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ER alpha. Finally, an MDA-MB-231-derived cell line that stably expressed shIFI16 or shMTA1 was more susceptible to tamoxifen-induced growth inhibition in in vitro and in vivo experiments. Taken together, our findings suggest that theMTA1-TFAP2C or the MTA1-IFI16 complex may contribute to the epigenetic regulation of ESR1 expression in breast cancer and may determine the chemosensitivity of tumors to tamoxifen therapy in patients with breast cancer. (c) 2014 AACR.