Valproic acid restores ERα and antiestrogen sensitivity to ERα-negative breast cancer cells
Valproic acid restores ERα and antiestrogen sensitivity to ERα-negative breast cancer cells
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DOI：
10.1016/j.mce.2009.09.011
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发表时间：
2010-01-15
影响因子：
4.1
通讯作者：
Boccuzzi, G.
中科院分区：
文献类型：
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作者：
Fortunati, N.;Bertino, S.;Boccuzzi, G.
组蛋白去乙酰化酶抑制剂（HDIs）是治疗乳腺癌的重要药物，其中雌激素受体α（ER α）可以通过表观遗传修饰而沉默。我们报告了临床上可用的HDI，丙戊酸（VPA），对ER阴性乳腺癌细胞MDA-MB-231中ER α表达和功能的影响。VPA诱导ER β mRNA和蛋白表达，而不改变ER β。在VPA处理的细胞中，我们还观察到：（1）在雌激素反应性最小启动子控制下的荧光素酶基因转染后，对雌二醇的正确转录反应（ERE-TKluc）;（2）ER相关转录因子FoxA 1的表达增加;（3）雌二醇诱导的几个雌激素调节基因的上调（例如pS2，孕酮受体）;（4）他莫昔芬对细胞生长的抑制作用。总之，诱导ER α和FoxA 1的HDI VPA赋予MDA-MB 231细胞雌激素敏感的“表型”，恢复其对抗雌激素治疗的敏感性。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor a (ER alpha) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ER alpha expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ER(x mRNA and protein, while did not modify ER beta. In VPA-treated cells, we also observed: (1) a correct transcriptional response to estradiol after transfection with the luciferase gene under the control of an estrogen-responsive minimal promoter (ERE-TKluc); (2) increased expression of the ER-related transcription factor FoxA1; (3) estradiol-induced up-regulation of several estrogen-regulated genes (e.g. pS2, progesterone receptor); (4) inhibitory effect of tamoxifen on cell growth. In conclusion, the HDI VPA, inducing ER alpha and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive "phenotype", restoring their sensitivity to antiestrogen therapy. (C) 2009 Elsevier Ireland Ltd. All rights reserved.