Characterizing DNA methylation alterations from The Cancer Genome Atlas.
ABSTRACT The Cancer Genome Atlas (TCGA) Research Network is an ambitious multi-institutional consortium effort aimed at characterizing sequence, copy number, gene (mRNA) expression, microRNA expression, and DNA methylation alterations in 30 cancer types. TCGA data have become an extraordinary resource for basic, translational, and clinical researchers and have the potential to shape cancer diagnostic and treatment strategies. DNA methylation changes are integral to all aspects of cancer genomics and have been shown to have important associations with gene expression, sequence, and copy number changes. This Review highlights the knowledge gained from DNA methylation alterations in human cancers from TCGA.
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ABSTRACT: The field of epigenetics has exploded in the last two decades, with incredible advances in recent years driven by high-throughput sequencing studies. Cancer cells frequently exhibit marked changes in DNA methylation and histone modification during tumorigenesis and tumor progression. These changes in the cancer epigenome are thought to be important in initiating and maintaining malignancy, and pharmaceutical approaches targeting epigenome-modifying enzymes are an attractive therapeutic strategy. Early successes have been made with DNA-demethylating drugs in hematologic malignancies, and efforts are underway to target additional epigenetic regulators and a broader array of tumor types. The Reviews in this issue of the JCI highlight ongoing efforts in this burgeoning field to translate our understanding of the cancer epigenome into successful interventional strategies in the clinic.The Journal of clinical investigation 01/2014; 124(1):14-6. DOI:10.1172/JCI74145 · 13.77 Impact Factor
- Frontiers in Oncology 03/2014; 4:46. DOI:10.3389/fonc.2014.00046
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ABSTRACT: 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.Journal of Biological Chemistry 03/2014; 289(20). DOI:10.1074/jbc.M113.527671 · 4.60 Impact Factor