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Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

Tanja Rothhammer-Hampl1, Franziska Liesenberg2, Natalie Hansen2

  • 1Department of Neuropathology, Regensburg University Hospital, 93053 Regensburg, Germany.

Cancers
|October 23, 2021
PubMed

Insights

DIRAS-1 and DIRAS-2 are frequently downregulated in gliomas due to epigenetic changes like promoter hypermethylation and histone modifications. Restoring their expression increases sensitivity to chemotherapy, suggesting a role in DNA damage response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • DIRAS-3 inactivation is linked to better survival in oligodendrogliomas.
  • The regulation and function of DIRAS family members DIRAS-1 and DIRAS-2 in gliomas remain largely unexplored.

Purpose of the Study:

  • To investigate the epigenetic regulation and functional role of DIRAS-1 and DIRAS-2 in glioma pathogenesis.
  • To determine if DIRAS-1 and DIRAS-2 expression influences response to chemotherapy.

Main Methods:

  • Analysis of DIRAS-1 and DIRAS-2 expression and promoter methylation in glioma samples and cell lines.
  • Treatment of glioblastoma cell lines with epigenetic modifiers (5-azacytidine, histone deacetylase inhibitor).
  • Assessment of glioblastoma cell sensitivity to lomustine and analysis of DNA damage markers.

Main Results:

  • DIRAS-1 and DIRAS-2 were significantly downregulated in glioma samples compared to non-neoplastic brain tissue, with DIRAS-2 showing 100% downregulation.
  • Promoter hypermethylation of DIRAS-1 and DIRAS-2 was observed in IDH-mutant gliomas, and re-expression was induced by 5-azacytidine.
  • Histone modifications also regulate DIRAS-1 and DIRAS-2 expression, with re-expression observed after treatment with a histone deacetylase inhibitor.
  • Overexpression of DIRAS-1 and DIRAS-2 enhanced glioblastoma cell sensitivity to lomustine and may be involved in p53-dependent DNA damage response.

Conclusions:

  • DIRAS-1 and DIRAS-2 are epigenetically silenced in gliomas through promoter hypermethylation and altered histone modifications.
  • Restoring DIRAS-1 and DIRAS-2 expression sensitizes glioblastoma cells to alkylating chemotherapy, highlighting their potential as therapeutic targets.
Keywords:
chromatinglioblastomahistone modificationlomustinemethylationp53

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