Cacan Ercan, Ali Mourad W, Boyd Nathaniel H, Hooks Shelley B, Greer Susanna F
Division of Cellular Biology and Immunology, Center for Inflammation, Immunity and Infection, Department of Biology, Georgia State University, Atlanta, Georgia, United States of America.
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia, United States of America.
PLoS One. 2014 Jan 27;9(1):e87455. doi: 10.1371/journal.pone.0087455. eCollection 2014.
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.
RGS10是卵巢癌中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转录本表达受到抑制。RGS10的抑制是由于DNA高甲基化和组蛋白去乙酰化，这是癌症进展过程中导致肿瘤抑制基因沉默的两个重要机制。在此，我们全面研究了化疗耐药的A2780-AD卵巢癌细胞中RGS10表达的表观遗传沉默的分子机制。我们鉴定出两个重要的表观遗传调节因子HDAC1和DNMT1，它们在化疗耐药的卵巢癌细胞中与RGS10启动子表现出异常关联。敲低HDAC1或DNMT1的表达，以及对DNMT或HDAC酶活性的药物抑制，均显著增加RGS10表达和顺铂介导的细胞死亡。最后，敲低DNMT1也会减少化疗耐药细胞中HDAC1与RGS10启动子的结合，表明HDAC1募集到RGS10启动子需要DNMT1的活性。我们的结果表明，HDAC1和DNMT1在获得性化疗耐药过程中促成了RGS10的抑制，并支持将抑制HDAC1和DNMT1作为克服卵巢癌化疗耐药的辅助治疗方法。
