SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation

Fahey, Catherine C.; Davis, Ian J.

doi:10.1101/cshperspect.a026468

Cited by 65 publications

(53 citation statements)

References 107 publications

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“…Survival analysis, prognosis of each group of patients examined using Kaplan-Meier survival estimators, and survival outcomes of the groups compared by log-rank tests revealed that SETD2 should be considered as a favorable prognostic gene and ATG12 as an unfavorable prognostic gene for ccRCC patients. cancer type 8,50 . Furthermore, these mutations correlate with aggressive clinicophatological features, and are associated with an unfavorable prognosis in patients with ccRCC 10-12 .…”

Section: Discussionmentioning

confidence: 99%

SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

et al. 2020

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Inactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC). SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values. Targeting autophagy, a conserved catabolic process with critical functions in maintenance of cellular homeostasis and cell conservation under stress condition, is emerging as a potential therapeutic strategy to combat ccRCC. Epigenetics-based pathways are now appreciated as key components in the regulation of autophagy. However, whether loss of function in the SETD2 histone modifying enzyme occurring in ccRCC cells may impact on their ability to undergo autophagy remained to be explored. Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12containing complex, distinct from the ATG5-ATG12 complex. Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process. Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells. The defect in the ATG12dependent conjugation system was found to be associated with a decrease autophagic flux, in accord with the role for this ubiquitin-like protein conjugation system in autophagosome formation and expansion. Finally, we report that SETD2 and ATG12 gene expression levels are associated with favorable respective unfavorable prognosis in ccRCC patients. Collectively, our findings bring further argument for considering the SETD2 gene status of ccRCC tumors, when therapeutic interventions, such as targeting the autophagic process, are considered to combat these kidney cancers.

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Section: Discussionmentioning

confidence: 99%

SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

et al. 2020

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“…Relatively high frequencies of loss-of-function SETD2 mutations have been reported in many tumor types, including acute lymphoblastic (10%) and myeloid leukemias (6%), adenocarcinoma of the lung (5%), and above all, clear cell renal cell carcinoma (15-20%), where SETD2 mutations have also been linked to advanced clinical stage at diagnosis and poor prognosis [11]. In addition, certain tumors harbor mutations involving the methyl acceptor site of H3K36 and adjacent amino-acid residues in histone H3.3, which also diminish H3K36me3 [12,13]. In thyroid cancers, however, loss-of-function SETD2 mutations appear to be fairly rare; they were found in only 0.9% of the aggressive forms of thyroid cancer analyzed by Landa et al [14].…”

Section: Introductionmentioning

confidence: 99%

Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid

Pecce

Verrienti

Abballe

et al. 2020

Cancers

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Hürthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. In both cases, metastatic tissues harbored a mutation of SETD2, each resulting in loss of the SRI and WW domains of SETD2, a methyltransferase that trimethylates H3K36 (H3K36me3) and also interacts with p53 to promote its stability. Functional studies of the novel p.D1890fs6* mutation (case 1) revealed significantly reduced H3K36me3 levels in SETD2-mutated tissue and primary cell cultures and decreased levels of the active form of p53. Restoration of SETD2-wildtype expression in the SETD2-mutant cells significantly reduced the expression of four well-known stemness markers (OCT-4, SOX2, IPF1, Goosecoid). These findings suggest potential roles for SETD2 loss-of-function mutations in HCC progression, possibly involving p53 destabilization and promotion of stemness. Their prevalence and potential treatment implications in thyroid cancer, especially HCC, require further study.

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“…Here, we summarize the recent progress regarding the regulation of H3K36 methyltransferase activity and their roles in transcription. Notably, H3K36 methylation also participates in other aspects of chromatin events such as DNA repair and mRNA splicing, discussion of which is beyond the scope of this review, but has been reviewed by others (Fahey and Davis 2017 ; Li 2013 ; McDaniel and Strahl 2017 ; Wagner and Carpenter 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Roles of H3K36-specific histone methyltransferases in transcription: antagonizing silencing and safeguarding transcription fidelity

Chang

Zhu

2018

Biophys Rep

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Histone H3K36 methylation is well-known for its role in active transcription. In Saccharomyces cerevisiae, H3K36 methylation is mediated solely by SET2 during transcription elongation. In metazoans, multiple H3K36-specific methyltransferases exist and contribute to distinct biochemical activities and subsequent functions. In this review, we focus on the H3K36-specific histone methyltransferases in metazoans, and discuss their enzymatic activity regulation and their roles in antagonizing Polycomb silencing and safeguarding transcription fidelity.

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SETting the Stage for Cancer Development: SETD2 and the Consequences of Lost Methylation

Cited by 65 publications

References 107 publications

SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12

Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid

Roles of H3K36-specific histone methyltransferases in transcription: antagonizing silencing and safeguarding transcription fidelity

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