Multi-omics analysis identifies glioblastoma dependency on H3K9me3 methyltransferase activity.

in NPJ precision oncology by Qiqi Xie, Yuanning Du, Sugata Ghosh, Saranya Rajendran, Aaron A Cohen-Gadol, José-Manuel Baizabal, Kenneth P Nephew, Leng Han, Jia Shen

TLDR

  • The study identifies the H3K9me3 methyltransferase signature as a prognostic factor and potential therapeutic target in glioblastoma and other cancers.

Abstract

Histone H3 lysine 9 dimethylation and trimethylation (H3K9me2/3) are prevalent in human genomes, especially in heterochromatin and specific euchromatic genes. Methylation of H3K9 is modulated by enzymes such as SUV39H1, SUV39H2, SETDB1, SETDB2, and EHMT1/2, which influence cancer progression. This study reveals differential expression of these six H3K9 methyltransferases in tumors, with SUV39H1, SUV39H2, and SETDB1 showing significant links to cancer phenotypes. We developed the "H3K9me3 MtSig" (H3K9me3 methyltransferases signature) based on these findings. H3K9me3 MtSig is unique to various tumors, with prognostic significance and associations with key signaling pathways, especially in glioblastoma (GBM). Elevated H3K9me3 MtSig was observed in GBM samples, correlating with the G2/M cell cycle and reduced immune responses. H3K9me3-mediated repetitive sequence silencing by H3K9me3 MtSig contributed to these phenotypes, and inhibiting H3K9me3 MtSig in patient-derived GBM cells suppressed proliferation and increased immune responses. H3K9me3 MtSig serves as an independent prognostic factor and potential therapeutic target.

Overview

  • The study examines the role of histone H3 lysine 9 dimethylation and trimethylation (H3K9me2/3) in cancer, specifically focusing on the expression of six H3K9 methyltransferases.
  • The study aims to identify the H3K9 methyltransferase signature (MtSig) and its associations with cancer phenotypes, as well as its potential as a prognostic factor and therapeutic target.
  • The study employs patient-derived glioblastoma (GBM) cells and gene expression analysis to investigate the correlations between H3K9me3 MtSig and cancer progression.

Comparative Analysis & Findings

  • The study finds that SUV39H1, SUV39H2, and SETDB1 show significant links to cancer phenotypes, suggesting their potential role as prognostic biomarkers.
  • The H3K9me3 MtSig is unique to various tumors, including GBM, and is associated with prognostic significance and key signaling pathways.
  • In GBM samples, elevated H3K9me3 MtSig correlates with the G2/M cell cycle and reduced immune responses, indicating its potential role in cancer progression.

Implications and Future Directions

  • The study suggests that H3K9me3 MtSig serves as an independent prognostic factor, offering potential therapeutic targeting opportunities.
  • Future studies could investigate the specific mechanisms by which H3K9me3 MtSig regulates gene expression and cancer progression.
  • The study's findings could be expanded to other cancer types, exploring the potential associations between H3K9me3 MtSig and cancer progression.
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