Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma

Tiedemann, Rochelle L.; Hlady, Ryan A.; Hanavan, Paul D.; Lake, Douglas F.; Tibes, Raoul; Lee, Jeong Heon; Choi, Jeong Hyeon; Ho, Thai H.; Robertson, Keith D.

doi:10.18632/oncotarget.6481

Cited by 54 publications

(57 citation statements)

References 51 publications

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“…Finally, tumors with C-CIMP showed enrichment with BAP1 and SETD2 mutations consistent with Sato dataset (8). Consistent with these data, Tiedemann and colleagues showed that SETD2-depleted cell lines exhibit a DNA hypermethylation phenotype coinciding with ectopic gains in H3K36me3 (26). Likewise, SETD2 -mutant primary ccRCC, papillary RCCs, and lung adenocarcinomes all demonstrated a DNA hypermethylation phenotype that segregated tumors by SETD2 genotype (26).…”

Section: Discussionmentioning

confidence: 67%

“…Consistent with these data, Tiedemann and colleagues showed that SETD2-depleted cell lines exhibit a DNA hypermethylation phenotype coinciding with ectopic gains in H3K36me3 (26). Likewise, SETD2 -mutant primary ccRCC, papillary RCCs, and lung adenocarcinomes all demonstrated a DNA hypermethylation phenotype that segregated tumors by SETD2 genotype (26). Mechanistic data are further needed to clarify the link between H3K36 methylation and CpG island methylation.…”

Section: Discussionmentioning

confidence: 67%

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NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas

Zhang

Mouawad

et al. 2017

Cancer Research

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Extensive dysregulation of chromatin-modifying genes in dear cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the cross-talk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear cell CpG island methylatorphenotype (C-CIMP) subgroup associated with promoter methylation of VEGF genes (FLT4, FLT1, and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the his-tone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets. NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of NSD1 displayed a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome. Thus, we concluded that epigenetic silencing of genes involved in angio-genesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss of function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 67%

NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas

Zhang

Mouawad

et al. 2017

Cancer Research

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“…In contrast, the SETD2 mutant tumors displayed a unique signature pattern of global DNA hypomethylation at non-promoter regions that distinguished them from other tumors. The implications of this remain uncertain, although recent studies have demonstrated that SETD2 mutations alter chromatin accessibility (33) and that expanded methylation coordinated with changes in histone methylation across the genome (34). As mutations in these chromatin-regulators were associated with altered expression patterns in a large number of other genes, chromatin remodeling appears to play a key role in the progression of clear cell RCC.…”

Section: Clear Cell Renal Cell Carcinoma (Ccrcc or Kirc)mentioning

confidence: 99%

Insights into the Genetic Basis of the Renal Cell Carcinomas from The Cancer Genome Atlas

Weyandt

Rathmell

2016

Molecular Cancer Research

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The renal cell carcinomas, clear cell, papillary, and chromophobe, have recently undergone an unmatched genomic characterization by The Cancer Genome Atlas (TCGA). This analysis has revealed new insights into each of these malignancies, and underscores the unique biology of clear cell, papillary, and chromophobe renal cell carcinoma. Themes that have emerged include distinct mechanisms of metabolic dysregulation and common mutations in chromatin modifier genes. Importantly, the papillary renal cell carcinoma classification encompasses a heterogeneous group of diseases, each with highly distinct genetic and molecular features. In conclusion, this review summarizes renal cell carcinomas which represent a diverse set of malignancies, each with novel biological programs that define new paradigms for cancer biology.

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“…The molecular mechanisms underlying SETD2's suppression of renal cancer reflect the physiological functions of H3K36 methylation in transcript processing and genome integrity, as outlined above. Briefly, loss of function of SETD2 in ccRCC results in defects in DNA repair, nucleosome dynamics, RNA processing and DNA methylation [102][103][104][105]. …”

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confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma

Cited by 54 publications

References 51 publications

NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas

NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas

Insights into the Genetic Basis of the Renal Cell Carcinomas from The Cancer Genome Atlas

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

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