Hwang Clara, Giri Veda N, Wilkinson John C, Wright Casey W, Wilkinson Amanda S, Cooney Kathleen A, Duckett Colin S
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Breast Cancer Res Treat. 2008 Jan;107(2):235-42. doi: 10.1007/s10549-007-9542-7. Epub 2007 Apr 24.
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase polycomb group (PcG) protein, which has been implicated in the process of cellular differentiation and cancer progression for both breast and prostate cancer. Although transcriptional repression by histone modification appears to contribute to the process of cellular differentiation, it is unclear what mediates the specificity of PcG proteins. Since EZH2 requires a binding partner for its histone methyltransferase activity, we surmised that evaluating interacting proteins might shed light on how the activity of EZH2 is regulated. Here we describe the identification of a novel binding partner of EZH2, the repressor of estrogen receptor activity (REA). REA functions as a transcriptional corepressor of the estrogen receptor and can potentiate the effect of anti-estrogens. REA expression levels have also previously been associated with the degree of differentiation of human breast cancers. We show here that EZH2 can also mediate the repression of estrogen-dependent transcription, and that moreover, the ability of both REA and EZH2 to repress estrogen-dependent transcription are mutually dependent. These data suggest that EZH2 may be recruited to specific target genes by its interaction with the estrogen receptor corepressor REA. The identification of a novel interaction between EZH2 and REA, two transcription factors that have been linked to breast cancer carcinogenesis, may lead to further insights into the process of deregulated gene expression in breast cancer.
zeste同源物增强子2（EZH2）是一种组蛋白甲基转移酶多梳蛋白家族（PcG）蛋白，它与乳腺癌和前列腺癌的细胞分化及癌症进展过程有关。虽然组蛋白修饰介导的转录抑制似乎参与了细胞分化过程，但尚不清楚是什么介导了PcG蛋白的特异性。由于EZH2的组蛋白甲基转移酶活性需要一个结合伴侣，我们推测评估其相互作用蛋白可能有助于揭示EZH2的活性是如何被调控的。在此，我们描述了EZH2一种新的结合伴侣——雌激素受体活性抑制因子（REA）的鉴定。REA作为雌激素受体的转录共抑制因子发挥作用，并且能够增强抗雌激素的作用。REA的表达水平此前也与人乳腺癌的分化程度相关。我们在此表明，EZH2也能够介导雌激素依赖性转录的抑制，而且，REA和EZH2抑制雌激素依赖性转录的能力是相互依赖的。这些数据表明，EZH2可能通过与雌激素受体共抑制因子REA相互作用而被招募至特定的靶基因。EZH2和REA这两个与乳腺癌致癌作用相关的转录因子之间新相互作用的鉴定，可能会为深入了解乳腺癌中基因表达失调的过程带来更多见解。
