Abstract
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.
Highlights
Ovarian cancer is one of the deadliest gynecological cancers, with a 60% mortality rate in patients and a 5-year survival rate of lower than 30% in advanced stage disease [1]
We identify two important epigenetic regulators, HDAC1 and DNMT1, which are highly associated with the RGS10 promoter in chemoresistant ovarian cancer cells
Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support growing evidence that inhibition of HDAC1/DNMT1 represent novel therapeutic approaches to overcoming ovarian cancer chemoresistance
Summary
Ovarian cancer is one of the deadliest gynecological cancers, with a 60% mortality rate in patients and a 5-year survival rate of lower than 30% in advanced stage disease [1]. The high mortality rate is due in large part to the development of resistance to chemotherapeutic drugs [2,3]. Activation of GPCRs by growth factors such as Lysophosphatidic acid (LPA) triggers survival signaling pathways that drive resistance to chemotherapeutic drugs such as cisplatin and taxane [6]. RGS proteins inhibit Gprotein signaling pathways by directly binding to the activated Ga subunit of G-proteins to accelerate hydrolysis of GTP into GDP, which returns G-proteins to an inactive state [7,8,9,10]. Recent reports indicate that RGS proteins inhibit breast, lung, prostate, and ovarian cancer cell growth through inhibition of GPCRs signaling pathways [2,11,12,13,14,15]
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