Abstract
Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1, SETD2 and BAP1, are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC.
Highlights
Kidney cancers account for the 7th and 10th most common malignancies in males and females, respectively, in the US according to estimated new cases in 2014 [1]
Little is known about the dysregulation of histone marks in clear cell Renal cell carcinoma (RCC) (ccRCC); it has been suggested that histone H3K9 acetylation is reduced in 85% of the ccRCCs compared to corresponding non-neoplastic tissue [158]
Another histone deacetylases (HDACs) inhibitor, panobinostat, has been reported to decrease hypoxia-induced cisplatin resistance in lung cancer cells by promoting HIFα destabilization [247]. These findings suggest that application of HDAC inhibitors in von Hippel-Lindau (VHL) deficient ccRCC could potentially render tumors chemosensitive by HIFα destabilization countering the resistance that exists in ccRCC currently
Summary
Kidney cancers account for the 7th and 10th most common malignancies in males and females, respectively, in the US according to estimated new cases in 2014 [1]. Numerous genes that are involved in the regulation of epigenetic modifications were discovered to be commonly mutated in RCC tumors. This pointed to the notion that abnormalities of epigenetic modifiers are likely among the key molecular driving factors of RCC. Epigenetic factors including DNA methylation patterns and histone modifications have a central role in the regulation of global and local gene expression [32,33]. Deregulation of these epigenetic regulatory mechanisms is involved in tumorigenesis of different cancers including RCC [32,33]. HIFs regulate genes that function in glucose uptake and metabolism, control of extracellular pH, erythropoiesis and angiogenesis, mitogenesis and apoptosis [23,38,41,47,50]
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