Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor α
Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor α
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DOI：
10.1002/ijc.11403
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发表时间：
2003-11-10
影响因子：
6.4
通讯作者：
Avraham, HK
中科院分区：
文献类型：
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作者：
Kawai, H;Li, HC;Avraham, HK
17β-雌二醇与雌激素受体α(ER-α)的相互作用在乳腺癌的发生和治疗中起着重要作用。ER-α是乳腺癌中一个重要的生长调控基因，其表达水平与乳腺癌患者的预后和治疗结果密切相关。ER-α在乳腺上皮细胞中的表达缺失是乳腺癌进展的关键。然而，这种丢失的潜在分子机制还不清楚。组蛋白脱乙酰酶(HDAC)参与染色质组装的改变和肿瘤的发生。我们发现组蛋白脱乙酰酶I(HDAC1)在体内外与ER-α相互作用，并抑制ER-α的转录活性。HDAC I与ER-α的相互作用是由ER-α的AF-2和DBD结构域介导的。我们在乳腺癌细胞中观察到HDAC I与ER-α的内源性相互作用，这种作用在雌激素存在的情况下会减少。有趣的是，与对照MCF-7细胞相比，稳定表达HDACi的MCF-7克隆诱导ER-α的丢失，细胞增殖和集落形成显著增加，而HDAC特异性抑制剂曲古菌素A(TSA)处理稳定的MCF-7克隆诱导ER-αmRNA和蛋白的重新表达。我们的发现有力地表明，HDAC I通过促进细胞增殖，同时减少ER-a蛋白的表达和转录活性来影响乳腺癌的进展。因此，HDAC I可能成为治疗ER阴性乳腺癌的潜在靶点。(C)2003年Wiley-Liss，Inc.
The interaction between 17beta-estradiol and estrogen receptor alpha (ER-alpha) plays an important role in breast carcinogenesis and breast cancer treatment. ER-alpha is a critical growth regulatory gene in breast cancer and its expression level is tightly linked to the prognosis and treatment outcomes of breast cancer patients. Loss of ER-alpha expression in breast epithelial cells is critical for breast cancer progression. The underlying molecular mechanisms for this loss, however, are poorly defined. Histone deacetylases (HDACs) are implicated in the alteration of chromatin assembly and tumorigenesis. We show that histone deacetylase I (HDAC 1) interacts with ER-alpha in vitro and in vivo and suppresses ER-alpha transcription activity. The interaction of HDAC I with ER-alpha was mediated by the AF-2 and DBD domains of ER-alpha. We observed an endogenous interaction of HDAC I with ER-alpha in breast cancer cells, which was decreased in the presence of estrogen. Interestingly, overexpression of HDACI in stable transfected MCF-7 clones induced loss of ER-alpha and significantly increased cell proliferation and colony formation, as compared to the control MCF-7 cells, whereas treatment of stable MCF-7 clones with the HDAC specific inhibitor trichostatin A (TSA) induced re-expression of ER-alpha mRNA and protein. Our findings strongly suggest that HDAC I affects breast cancer progression by promoting cellular proliferation in association with a reduction in both ER-a protein expression and transcriptional activity. Thus, HDAC I may be a potential target for therapeutic intervention in the treatment of a subset of ER-negative breast cancers. (C) 2003 Wiley-Liss, Inc.