Epigenetic regulation in RCC: opportunities for therapeutic intervention?

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Abstract

Renal cell carcinoma (RCC) is a constellation of malignancies of different histological subtypes arising from the renal parenchyma. The clear cell histological subtype (ccRCC) accounts for around 75% of RCCs and is characterized by distinct genetic abnormalities, of which the loss of function of the von Hippel–Lindau (VHL) tumor suppressor gene is the most common. Inactivation of other tumor suppressor genes such as SETD2, KDM6A, KDM5C and PBRM1 has been reported in ccRCC—notably, the proteins encoded by these genes are involved in histone and chromatin regulation. Furthermore, the PBRM1 and SETD2 genes are located on the short arm of chromosome 3 near the VHL locus. Chromatin and histones modify gene expression and, as a consequence, their function is tightly regulated. Data from RNA interference (RNAi) assays suggest that loss of function of PBRM1 drives proliferation and growth of ccRCC, but the clinical relevance of this is unclear and restoring the function of these genes for therapeutic purposes is likely to be challenging. An improved understanding of histone and chromatin regulation in RCC biology and the consequences of intratumor heterogeneity might identify novel targets in RCC and present alternative therapeutic opportunities.

Key Points

  • Clear cell renal cell carcinoma (ccRCC) accounts for about 75% of all RCCs

  • Newly reported mutations of tumor suppressor genes SETD2, KDM6A and KDM5C, which encode proteins involved in histone modification, have been shown to occur in ccRCC

  • Chromosomal locus 3p21, where VHL, BAP1, SETD2 and PBRM1 reside, highlights a hot spot for mutations of genes involved in ccRCC

  • Newly identified somatic mutations in histone modifying enzymes suggest that chromatin and histone modifications might have important roles in the pathogenesis of ccRCC

  • A better understanding of the roles of histone modification provides a potential therapeutic target in ccRCC

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Figure 1: Structure of chromatin.
Figure 2: Map of histone methylation and acetylation in renal cell carcinoma.
Figure 3: Deletions and mutations of VHL, PBRM1, BAP1 and SETD2 genes on chromosomal locus 3p.

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J. Larkin, X. Y. Goh and M. Vetter contributed equally to the writing of this manuscript, researching data for the article, writing the manuscript and making a substantial contribution to discussion of content, as well as reviewing and editing the manuscript before submission. L. Pickering reviewed and edited the article before submission. C. Swanton researched data for the article, made a substantial contribution to discussion of content and reviewed and edited the manuscript before submission.

Correspondence to Charles Swanton.

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