Role of DNA methylation in renal cell carcinoma

Abstract

Alterations in DNA methylation are seen in cancers and have also been examined in clear cell renal cell carcinoma (ccRCC). Numerous tumor suppressor genes have been reported to be partially or completely silenced due to hypermethylation of their promoters in single-locus studies, and the use of hypomethylating agents has been shown to restore the expression of many of these genes in vitro. In particular, members of the Wnt and TGF-beta pathways, pro-apoptotic genes such as APAF-1 and negative cell-cycle regulators such as KILLIN have been shown to be epigenetically silenced in numerous studies in ccRCC. Recently, TCGA analysis of a large cohort of ccRCC samples demonstrated that aberrant hypermethylation correlated with the stage and grade in kidney cancer. Our genome-wide studies also revealed aberrant widespread hypermethylation that affected regulatory regions of the kidney genome in ccRCC. We also observed that aberrant enhancer hypermethylation was predictive of adverse prognosis in ccRCC. Recent discovery of mutations affecting epigenetic regulators reinforces the importance of these changes in the pathophysiology of ccRCC and points to the potential of epigenetic modulators in the treatment of this malignancy.

Upregulation of TET Activity with Ascorbic Acid Induces Epigenetic Modulation of Lymphoma Cells

“…Considering the TET-mediated demethylation effect, AA could potentially also be a promising therapeutic strategy against other hypermethylated malignancies such as chronic myelomonogenous leukemia (60-70% of cases with TET2 mutations), 34 myelodysplastic syndrome, 35 TET-2 mutated and IDH mutated acute myelogeneous leukemia (2-hydroxyglutarate mediated suppression of TET), 36,37 clear cell renal cell carcinoma, 38,39 and succinate dehydrogenase mutated paraganglioma. 40 Given that most of these TET-2 mutations are uniallelic, it is possible that the activity of the wild-type copy could be optimized by AA and produce therapeutic benefit.…”

Inhibition of canonical WNT/β-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells

“…Several classes of secreted proteins exist as natural antagonists for WNT signaling, such as Dickkopf-related proteins (DKKs) and secreted Frizzled-related proteins (sFRPs). However, the promoters of several endogenous WNT antagonists are epigenetically silenced in primary RCC samples when compared to the corresponding normal renal tissue samples [33]. These alterations converge into abnormal activation of WNT signaling in RCCs, promoting tumorigenicity, proliferative rate, metastatic potential, and insensitivity to radio-chemotherapy.…”

Renal Carcinogenesis, Tumor Heterogeneity, and Reactive Oxygen Species: Tactics Evolved

“…The role of NOX oxidases or ETC-derived ROS as an upstream direct or indirect regulator of DNA methylation or as a downstream target of methylation is unknown and needs investigation. Other recent reviews outlining large datasets evaluating DNA methylation as a regulator of the epigenetic landscape are listed (65,82,132). Epigenetic-driven gene expression profiles are dynamic, and, therefore, the complexity added due to obesity (59) and diabetes (126) needs to be evaluated systematically.…”