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Ras-induced Epigenetic Inactivation of the RRAD ( Ras-related Associated with Diabetes) Gene Promotes Glucose Uptake in a Human Ovarian Cancer Model
Wang, Yan1,2; Li, Guiling3; Mao, Fengbiao2,4; Li, Xianfeng5; Liu, Qi3; Chen, Lin4; Lv, Lu3; Wang, Xin3; Wu, Jinyu3; Dai, Wei1; Wang, Guan6; Zhao, Enfeng6; Tang, Kai-Fu3; Sun, Zhong Sheng3,4
AbstractBackground: Increased glucose uptake is essential for carcinogenesis. Results: Ras(V12)-induced epigenetic inactivation of RRAD promotes glucose uptake and tumor formation. Conclusion: RRAD might act as a functional tumor suppressor by inhibiting glucose uptake. Significance: Down-regulation of RRAD in tumor tissues might be associated with the Warburg effect. RRAD (Ras-related associated with diabetes) 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 Ras(V12)-transformed human ovarian epithelial cell line) with T29 (an immortalized but non-transformed cell line) through reduced representation bisulfite sequencing and digital gene expression. We found that Ras(V12)-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 resulted in demethylation in the RRAD promoter and restored RRAD expression in T29H cells. Additionally, treatment with farnesyltransferase inhibitor FTI277 resulted in restored RRAD expression and inhibited DNA methytransferase 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 that RRAD is a tumor suppressor gene. Our results indicate that Ras(V12)-mediated oncogenic transformation induces RRAD epigenetic inactivation, which in turn promotes glucose uptake and may contribute to ovarian cancer tumorigenesis.
KeywordDNA Methylation Metabolism Ovarian Cancer Ras Tumor Suppressor Gene Oncogenic Transformation RRAD
2014-05-16
Language英语
Source PublicationJOURNAL OF BIOLOGICAL CHEMISTRY
ISSN0021-9258
Volume289Issue:20Pages:14225-14238
SubtypeArticle
Indexed BySCI
WOS IDWOS:000335984600048
Citation statistics
Cited Times:20[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.psych.ac.cn/handle/311026/13492
Collection健康与遗传心理学研究室
Affiliation1.Chinese Acad Sci, Inst Psychol, Beijing 100101, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100080, Peoples R China
3.Wenzhou Med Univ, Inst Genom Med, Wenzhou 325000, Zhejiang, Peoples R China
4.Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100101, Peoples R China
5.Cent S Univ, State Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China
6.Chinese Peoples Liberat Army, Gen Hosp, Dept Obstet & Gynecol, Beijing 100853, Peoples R China
First Author AffilicationInstitute of Psychology, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
Wang, Yan,Li, Guiling,Mao, Fengbiao,et al. Ras-induced Epigenetic Inactivation of the RRAD ( Ras-related Associated with Diabetes) Gene Promotes Glucose Uptake in a Human Ovarian Cancer Model[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2014,289(20):14225-14238.
APA Wang, Yan.,Li, Guiling.,Mao, Fengbiao.,Li, Xianfeng.,Liu, Qi.,...&Sun, Zhong Sheng.(2014).Ras-induced Epigenetic Inactivation of the RRAD ( Ras-related Associated with Diabetes) Gene Promotes Glucose Uptake in a Human Ovarian Cancer Model.JOURNAL OF BIOLOGICAL CHEMISTRY,289(20),14225-14238.
MLA Wang, Yan,et al."Ras-induced Epigenetic Inactivation of the RRAD ( Ras-related Associated with Diabetes) Gene Promotes Glucose Uptake in a Human Ovarian Cancer Model".JOURNAL OF BIOLOGICAL CHEMISTRY 289.20(2014):14225-14238.
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