Histone deacetylase inhibitor trichostatin a represses estrogen receptor α-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines
Histone deacetylase inhibitor trichostatin a represses estrogen receptor α-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines
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DOI：
10.1158/1078-0432.ccr-04-1023
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发表时间：
2004-12-01
影响因子：
11.5
通讯作者：
Vigushin, DM
中科院分区：
文献类型：
--
作者：
Alao, JP;Lam, EWF;Vigushin, DM
目的：雌激素受体α（ER α）阳性乳腺癌细胞系比ER α阴性细胞系对组蛋白去乙酰化酶抑制剂阿司他丁A（TSA）的抗增殖活性的敏感性高10倍。本研究的目的是探讨这种差异response.Experimental设计和结果的机制：在ER α阳性MCF-7细胞系，TSA抑制ER α和细胞周期蛋白D1的转录和诱导泛素依赖的蛋白酶体降解的细胞周期蛋白D1，导致主要的G（1）-S期细胞周期停滞。与此相反，在ER α阴性的MDA-MB-231细胞系中，细胞周期蛋白D1的降解被增强，但其转录不受TSA的影响，其停滞在G（2）-M期。细胞周期蛋白D1的降解涉及Skp 2/p45，一个监管组件的Skp 1/Cullin/F-盒复合物;沉默SKP 2基因表达的RNA干扰稳定细胞周期蛋白D1和废除细胞周期蛋白D1下调响应TSA.Conclusions：他莫昔芬已被证明能抑制ER α介导的细胞周期蛋白D1的转录，获得性耐药他莫昔芬与ER α独立的细胞周期蛋白D1上调的转变。综上所述，我们的数据表明TSA通过ER α依赖性和ER α非依赖性机制有效诱导细胞周期蛋白D1下调，为对抗雌激素抗性提供了重要的新策略。
Purpose: Estrogen receptor alpha (ERalpha)-positive breast cancer cell lines are up to 10 times more sensitive than ERalpha-negative cell lines to the antiproliferative activity of the histone deacetylase inhibitor trichostatin A (TSA). The purpose of the study was to investigate the mechanisms underlying this differential response.Experimental Design and Results: In the ERalpha-positive MCF-7 cell line, TSA repressed ERalpha and cyclin D1 transcription and induced ubiquitin dependent proteasomal degradation of cyclin D1, leading primarily to G(1)-S-phase cell cycle arrest. By contrast, cyclin D1 degradation was enhanced but its transcription unaffected by TSA in the ERalpha-negative MDA-MB-231 cell line, which arrested in G(2)-M phase. Cyclin D1 degradation involved Skp2/p45, a regulatory component of the Skp1/Cullin/F-box complex; silencing SKP2 gene expression by RNA interference stabilized cyclin D1 and abrogated the cyclin D1 down-regulation response to TSA.Conclusions: Tamoxifen has been shown to inhibit ERalpha-mediated cyclin D1 transcription, and acquired resistance to tamoxifen is associated with a shift to ERalpha-independent cyclin D1 up-regulation. Taken together, our data show that TSA effectively induces cyclin D1 down-regula-tion through both ERalpha-dependent and ERalpha-independent mechanisms, providing an important new strategy for combating resistance to antiestrogens.