Transcriptional suppression, DNA methylation, and histone deacetylation of the Regulator of G‐protein Signaling 10 (RGS10) gene in ovarian cancer cells

Mourad Wagdy Ali,Ercan Cacan,Yuying Liu,Susanna F Greer,Scott T Eblen,Shelley B Hooks

doi:10.1096/fasebj.27.1_supplement.1095.1

Abstract

Regulators of G‐Protein Signaling (RGS) Proteins suppress GPCR‐mediated growth and survival signaling in multiple cancers. We have shown that RGS10 is downregulated in ovarian cancer chemoresistance, and RGS10 expression levels alter ovarian cancer cell growth and sensitivity to cytotoxic drugs. This suggests that the suppression of RGS10 may contribute to ovarian cancer progression and the development of chemoresistance by indirectly amplifying GPCR‐mediated growth and survival signaling. The current study investigates the epigenetic regulation of RGS10 expression in ovarian cancer. RGS10 expression was reduced in clinical ovarian cancer and CAOV‐3 ovarian cancer cells compared to control immortalized ovarian surface epithelial (IOSE) cells. Histone acetylation at RGS10 promoters was decreased in CAOV‐3 compared to IOSE cells, with a corresponding increase in HDAC1 association. Similar loss of histone acetylation and increased HDAC1 binding was observed in chemoresistant versus chemosensitive ovarian cancer cells. Further, enhanced DNA methylation was observed in RGS10 promoter of chemoresistant cells. Our results suggest that epigenetic modifications correlate with the loss of RGS10 expression in ovarian cancer cells, and may contribute to the amplification of GPCR‐mediated growth and survival signaling. This research is funded by NIH and the Marsha Rivkin Center.

Highlights

Cancer cells exploit multiple receptor-mediated growth and survival signaling pathways to evade normal quiescence and cell death responses
To determine if Regulator of G-Protein Signaling 10 (RGS10) is downregulated in primary ovarian cancer cells, we immunoblotted lysates from the benign, immortalized immortalized ovarian surface epithelial (IOSE) cell and from six primary epithelial ovarian cancer cell samples isolated from patient ascites (Figure 1A)
RGS10 protein expression was markedly lower in cells from each patient, suggesting that RGS10 expression is suppressed in clinical ovarian cancer

Summary

Introduction

Cancer cells exploit multiple receptor-mediated growth and survival signaling pathways to evade normal quiescence and cell death responses. RGS10 transcript expression is downregulated in multiple models of acquired chemoresistance in ovarian cancer, and RGS10 expression levels alter ovarian cancer cell sensitivity to cisplatin and taxane cytotoxicity [10] These observations suggest that suppression of RGS10 expression may contribute to ovarian cancer progression and the development of chemoresistance by amplifying GPCR-mediated growth and survival signaling pathways. DNA methylation and DNMT expression increase in ovarian cancer progression [22], and histone deacetylases (HDACs) are overexpressed in ovarian cancer tissues [23] This suggests that epigenetic regulation of RGS genes may contribute to their dynamic expression in cancer progression. Our results suggest that epigenetic histone modifications may contribute to the loss of RGS10 expression in ovarian cancer cells, and that DNA methylation may contribute to further loss of expression during acquired chemoresistance

Experimental Procedures

Results

Discussion