Abstract POSTER-BIOL-1317: Releasing the brakes on ovarian cancer cell survival: epigenetic suppression of RGS10 in ovarian cancer chemoresistance

Abstract

Abstract G-protein signaling pathways promote cell survival, which is aberrantly enhanced in chemoresistant ovarian cancer. Regulator of G-protein Signaling (RGS) proteins limit the strength of G-protein signaling, and therefore indirectly control cell survival. We have previously shown that RGS10 suppresses ovarian cancer cell growth and limits survival in the presence of cytotoxic chemotherapeutic drugs. Further, we have shown that RGS10 expression is suppressed in cell models of ovarian cancer chemoresistance, suggesting that ovarian cancer cells silence RGS10 expression to release the brakes on their growth and survival. However, the mechanisms governing RGS10 expression in ovarian cancer cells are poorly understood. In this study, we fully investigate the molecular mechanism of RGS10 suppression in ovarian cancer acquired chemoresistance, revealing key roles for epigenetic regulation by DNA hypermethylation and histone deacetylation. Pharmacological inhibition of DNA methyl-transferases (DNMTs) increases RGS10 expression in chemoresistant ovarian cancer cells, suggesting potential regulation by DNA methylation. Further, bisulfite sequencing analysis identified a region of the RGS10-1 promoter with significantly enhanced DNA methylation in chemoresistant A2780-AD cells relative to parental A2780 cells. More marked differences are observed in histone acetylation of the RGS10-1 promoter. Acetylated histone H3 associates with the RGS10-1 promoter was significantly lower in A2780-AD cells compared to parental cells, with a corresponding increase in histone deacetylase (HDAC) enzyme association. Further, both HDAC1 and DNMT1 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 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 cooperatively 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. Citation Format: Shelley Hooks, PhD. Releasing the brakes on ovarian cancer cell survival: epigenetic suppression of RGS10 in ovarian cancer chemoresistance [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1317.