RGS10 suppression by DNA methylation is associated with low survival rates in colorectal carcinoma

Abstract

Colorectal cancer is known as the third most common cancer in both women and men. Genetic and epigenetic changes are major players contributing to colorectal carcinogenesis. Regulator of G-protein signaling 10 (RGS10) is a member of the RGS proteins, which negatively regulate several signaling pathways including cell survival and proliferation. We and others have previously shown that RGS10 expression is modulated by epigenetic modifications in ovarian cancer and suppression of RGS10 partially contributes to chemoresistance. Here, we further analyzed the roles and regulation of RGS10 in colon adenocarcinoma (COAD), using broad bioinformatics tools. We analyzed the expression profiles, promoter methylation state, prognostic value and effect of a hypomethylating agent on RGS10 expression. Results showed that RGS10 expression is higher in normal colon tissues than in tumor tissues. In addition, there is a negative correlation between DNA methylation and RGS10 transcript expression. We also observed that gene expression and promoter methylation of RGS10 in colorectal carcinoma patients were differently expressed depending on the tumor stage and microsatellite stability. DNA methylation was significantly increased in 18 probes of RGS10, which belongs to the high-risk group in COAD. In addition, pharmacological inhibition of DNA methyltransferase with decitabine reduced the six CpGsite-specific RGS10 hypermethylation in COAD. We also experimentally confirmed that RGS10 promoter activity was inhibited by treatment with decitabine in the HT-29 colorectal cell line. We further showed that decitabine treatment increases the RGS10 transcript expression in three different colorectal carcinoma cell lines. These results suggest that RGS10 expression is suppressed in the development of colorectal cancer and inhibition of DNA methylation may contribute to increasing overall survival rates of COAD patients.

Keywords: Colorectal carcinoma; DNA hypermethylation; Decitabine; RGS10; Survival rates.