Ras-induced epigenetic inactivation of Ras-related associated with diabetes gene (RRAD) promotes glucose uptake in a human ovarian cancer model [Metabolism]

March 19th, 2014 by Wang, Y., Li, G., Mao, F., Li, X., Liu, Q., Chen, L., Lv, L., Dai, W., Wang, G., Zhao, E., Tang, K.-F., Sun, Z. S.

Ras-related associated with diabetes (RRAD) is a small Ras-related GTPase that is frequently inactivated by DNA methylation of the CpG island in its promoter region in cancer tissues. However, the role of the methylation-induced RRAD inactivation in tumorigenesis remains unclear. In this study, the Ras regulated-transcriptome and epigenome were profiled by comparing T29H (a RasV12-transformed human ovarian epithelial cell line) with T29 (an immortalized but non-transformed cell line) through Reduced representation bisulfite sequencing (RRBS-seq) and Digital gene expression (DGE). We found that RasV12-mediated oncogenic transformation was accompanied by RRAD promoter hypermethylation and a concomitant loss of RRAD expression. In addition, we found that the RRAD promoter was hypermethylated and its transcription was reduced in ovarian cancer versus normal ovarian tissues. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) resulted in demethylation in RRAD promoter and restored RRAD expression in T29H cells. Additionally, treatment with farnesyltransferase inhibitor FTI277 resulted in restored RRAD expression and inhibited DNMTs expression and activity in T29H cells. By employing knockdown and overexpression techniques in T29 and T29H, respectively, we found that RRAD inhibited glucose uptake and lactate production by repressing the expression of glucose transporters. Finally, RRAD overexpression in T29H cells inhibited tumor formation in nude mice, suggesting RRAD is a tumor suppressor gene. Our results indicate that RasV12-mediated oncogenic transformation induces RRAD epigenetic inactivation, which in turn promotes glucose uptake and may contribute to ovarian cancer tumorigenesis.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Ras-induced epigenetic inactivation of Ras-related associated with diabetes gene (RRAD) promotes glucose uptake in a human ovarian cancer model [Metabolism]