Inhibition of HDAC1 and DNMT1 modulate RGS10 expression and decrease ovarian cancer chemoresistance.
Inhibition of HDAC1 and DNMT1 modulate RGS10 expression and decrease ovarian cancer chemoresistance.
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DOI：
10.1371/journal.pone.0087455
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Greer SF
中科院分区：
文献类型：
--
作者：
Cacan E;Ali MW;Boyd NH;Hooks SB;Greer SF
RGS10是卵巢癌细胞存活和化疗耐药的重要调节因子。我们最近发现，在卵巢癌获得性化疗耐药过程中，RGS10的转录表达受到抑制。RGS10的抑制是由于DNA高甲基化和组蛋白去乙酰化，这两个重要机制有助于在癌症进展过程中沉默肿瘤抑制基因。在这里，我们充分研究了在化疗耐药的A2780-AD卵巢癌细胞中RGS10表达的表观遗传沉默的分子机制。我们确定了两个重要的表观遗传调控因子，HDAC1和DNMT1，它们与化疗耐药的卵巢癌细胞中的RGS10启动子异常相关。抑制HDAC1或DNMT1的表达，以及药物抑制DNMT或HDAC的酶活性，显著增加RGS10的表达和顺铂介导的细胞死亡。最后，DNMT1基因敲除也减少了化疗耐药细胞中HDAC1与RGS10启动子的结合，表明HDAC1重新招募到RGS10启动子需要DNMT1的活性。我们的结果表明，HDAC1和DNMT1参与了获得性化疗耐药过程中RGS10的抑制，并支持抑制HDAC1和DNMT1作为克服卵巢癌化疗耐药的辅助治疗方法。
RGS10 is an important regulator of cell survival and chemoresistance in ovarian cancer. We recently showed that RGS10 transcript expression is suppressed during acquired chemoresistance in ovarian cancer. The suppression of RGS10 is due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to silencing of tumor suppressor genes during cancer progression. Here, we fully investigate the molecular mechanisms of epigenetic silencing of RGS10 expression in chemoresistant A2780-AD ovarian cancer cells. We identify two important epigenetic regulators, HDAC1 and DNMT1, that exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down also decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance.
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