Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling
Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling
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DOI：
10.1158/0008-5472.can-07-2822
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Munster, Pamela N.
中科院分区：
文献类型：
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作者：
Bicaku, Elona;Marchion, Douglas C.;Munster, Pamela N.
几种组蛋白去乙酰化酶（HDAC）参与雌激素受体（ER）介导的基因反式激活，HDAC抑制剂已被报道可以恢复对抗激素治疗的敏感性。ER的调节是治疗ER表达乳腺癌最有前途的方法。最近的研究进一步表明孕激素受体（PR）对ER信号传导的关键作用。虽然HDAC抑制剂调节ER，很少有人知道他们对PR的影响。我们评估了特定的HDAC同工酶的作用和它们对ER和PR信号传导的抑制作用及其在内分泌治疗中的重要性。个体HDAC同工酶对ER和PR表达的作用及其功能通过使用siRNA或药理学抑制消除选择的HDAC酶来评估。乳腺癌细胞系与HDAC抑制剂和抗雌激素，他莫昔芬，导致协同抗肿瘤活性，同时消耗ER和PR。选择性抑制HDAC 2，但不是HDAC 1或HDAC 6，足以增强他莫昔芬诱导的ER/PR阳性细胞凋亡。HDAC 1和HDAC 6的耗竭与ER的下调有关，但与PR无关。只有HDAC 2 siRNA的选择性耗竭下调了ER和PR的表达，并且足以增强他莫昔芬。HDAC 2的选择性耗竭导致ER和PR的同时耗竭，并增强了ER阳性细胞中抗激素治疗的效果。当HDAC抑制剂和激素治疗联合使用时，可以考虑对HDAC 2进行更有效的药理学抑制，并将HDAC 2和PR作为治疗靶点或作为激素治疗中的预测标志物进行评价。
Several histone deacetylases (HDAC) are involved in estrogen receptor (ER)-mediated gene transactivation, and HDAC inhibitors have been reported to restore sensitivity to antihormonal therapy. The modulation of ER is the most promising approach to ER-expressing breast cancers. Recent studies further suggest a critical role of the progesterone receptor (PR) on ER signaling. Although HDAC inhibitors modulate ER, little is known about their effects on PR. We evaluated the roles of specific HDAC isoenzymes and their inhibition on both ER and PR signaling and their importance in response to endocrine therapy. The roles of individual HDAC isoenzymes on ER and PR expression and their functions were evaluated by depletion of select HDAC enzymes using siRNA or pharmacologic inhibition. Cotreatment of breast cancer cell lines with HDAC inhibitors and the antiestrogen, tamoxifen, resulted in synergistic antitumor activity with simultaneous depletion of both ER and PR. Selective inhibition of HDAC2, but not HDAC1 or HDAC6, was sufficient to potentiate tamoxifen-induced apoptosis in ER/PR-positive cells. Depletion of HDAC1 and HDAC6 was associated with down-regulation of ER but not PR. Only the selective depletion of HDAC2 siRNA down-regulated both ER and PR expression, and was sufficient to potentiate tamoxifen. Selective depletion of HDAC2 resulted in simultaneous depletion of ER and PR, and potentiated the effects of antihormonal therapy in ER-positive cells. A more effective pharmacologic inhibition of HDAC2 and evaluation of HDAC2 and PR as therapeutic targets or as predictive markers in hormonal therapy may be considered when combining HDAC inhibitors and hormonal therapy.