Estrogen Receptor-β Modulation of the ERα-p53 Loop Regulating Gene Expression, Proliferation, and Apoptosis in Breast Cancer.
Estrogen Receptor-β Modulation of the ERα-p53 Loop Regulating Gene Expression, Proliferation, and Apoptosis in Breast Cancer.
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DOI：
10.1007/s12672-017-0298-1
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发表时间：
2017-08
影响因子：
3
通讯作者：
Katzenellenbogen BS
中科院分区：
文献类型：
--
作者：
Lu W;Katzenellenbogen BS
雌激素受体α(ERα)是乳腺癌中一个重要的转录调节因子，但雌激素通过ERα和ERβ两种雌激素受体介导其作用，这两种受体对基因表达和乳腺癌细胞的生存和生长具有截然不同的调控作用。在这里，我们研究了ERβ对乳腺癌中ERα-P53环的影响。我们发现ERβ可减弱ERα诱导的细胞增殖，增加细胞凋亡，并逆转ERα对转录的激活和抑制。此外，ERβ与P53在物理上相互作用，减少ERα-P53的结合，拮抗ERα-P53介导的转录调控。ERα指导SUV39H1/H2和组蛋白H3裂解9三甲基化(H3K9me3)异染色质组装在雌激素抑制的基因上，以沉默P53激活的转录。ERβ阳性细胞中ERα的存在通过下调SUV39H1和SUV39H2而取消了H3K9me3抑制异染色质的构象，从而释放了ERα诱导的转录阻断。此外，ERβ的存在刺激ERα抑制基因上组蛋白H3裂解酶4三甲基化(H3K4me3)和RNA聚合酶II(RNAPolII)的积累，诱导这些抑制基因转录的表观遗传激活，从而促进基于P53的肿瘤抑制。ERβ还减少了辅阻遏子N-COR和ERα对SMRT的募集，从而减弱了ERα和P53之间的串扰。总体而言，我们的数据揭示了ERβ的S在乳腺癌细胞中抗增殖和促凋亡作用的新机制，涉及p53和组蛋白甲基化的表观遗传学变化，这是这些细胞活动的基因调控的基础。
Estrogen receptor α (ERα) is a crucial transcriptional regulator in breast cancer, but estrogens mediate their effects through two estrogen receptors, ERα and ERβ, subtypes that have contrasting regulatory actions on gene expression and the survival and growth of breast cancer cells. Here, we examine the impact of ERβ on the ERα-p53 loop in breast cancer. We found that ERβ attenuates ERα-induced cell proliferation, increases apoptosis, and reverses transcriptional activation and repression by ERα. Further, ERβ physically interacts with p53, reduces ERα-p53 binding, and antagonizes ERα-p53-mediated transcriptional regulation. ERα directs SUV39H1/H2 and histone H3 lys9 trimethylation (H3K9me3) heterochromatin assembly at estrogen-repressed genes to silence p53-activated transcription. The copresence of ERβ in ERα-positive cells abrogates the H3K9me3 repressive heterochromatin conformation by downregulating SUV39H1 and SUV39H2, thereby releasing the ERα-induced transcriptional block. Furthermore, the presence of ERβ stimulates accumulation of histone H3 lys4 trimethylation (H3K4me3) and RNA polymerase II (RNA Pol II) on ERα-repressed genes, inducing H3K4me3-associated epigenetic activation of the transcription of these repressed genes that can promote p53-based tumor suppression. ERβ also reduced corepressor N-CoR and SMRT recruitment by ERα that could attenuate the crosstalk between ERα and p53. Overall, our data reveal a novel mechanism for ERβ’s anti-proliferative and pro-apoptotic effects in breast cancer cells involving p53 and epigenetic changes in histone methylation that underlie gene regulation of these cellular activities.
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影响因子：
7.4
作者：
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影响因子：
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作者：
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通讯作者：
VOGELSTEIN, B
影响因子：
64.5
作者：
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通讯作者：
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影响因子：
4.1
作者：
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通讯作者：
Katzenellenbogen, BS
DOI：
10.1073/pnas.1018858109
发表时间：
2012-10-30
影响因子：
11.1
作者：
Bailey, Shannon T.;Shin, Hyunjin;Brown, Myles
通讯作者：
Brown, Myles