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Updated: Jul 20, 2025

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A role for SETD2 loss in tumorigenesis through DNA methylation dysregulation

Hira Javaid1, Alessandro Barberis2, Olga Chervova3

  • 1Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.

BMC Cancer
|August 1, 2023
PubMed

Insights

Loss of SETD2, an enzyme regulating H3K36me3, disrupts DNA methylation in most cancers. This DNA methylation dysregulation impacts gene expression and cancer aggressiveness, suggesting a new role for SETD2 in tumorigenesis.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Genomics

Background:

  • SETD2 enzyme catalyzes H3K36me3, a histone modification linked to DNA methylation.
  • SETD2 mutations are common in various cancers, but their impact on DNA methylation and tumorigenesis remains unclear.

Purpose of the Study:

  • To investigate the functional consequences of SETD2 loss on DNA methylation across diverse cancer types.
  • To explore the association between SETD2-dependent DNA methylation changes and cancer aggressiveness, particularly in renal cancer.

Main Methods:

  • Pan-cancer analysis of SETD2 mutation and expression data alongside DNA methylation profiles.
  • Correlation analysis of DNA methylation changes with gene expression, including oncogenes, tumor suppressors, and invasion-related genes.
  • Machine learning approach to develop a DNA methylation signature for predicting SETD2 mutation status and patient prognosis.

Main Results:

  • SETD2 mutation or reduced expression correlates with DNA methylation dysregulation in 21 of 24 cancer types.
  • In renal cancer, altered DNA methylation due to SETD2 loss impacts expression of key genes like TP53, FOXO1, and CDK4, affecting neoplasm invasiveness.
  • A 3-CpG methylation signature accurately predicts SETD2 mutation status and patient prognosis.

Conclusions:

  • SETD2 loss contributes to tumorigenesis and cancer aggressiveness through DNA methylation dysregulation.
  • SETD2-dependent epigenetic alterations represent a potential therapeutic target in cancer.
Keywords:
DNA methylationH3K36me3Machine learning biomarkerRenal cancer biomarkerSETD2

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