Epigenetic Silencing of Death Receptor 4 Contributes to Resistance to TRAIL-Mediated Apoptosis in Gliomas

Strategic Insights -

Researchers at the University of Heidelberg in Germany have made a significant discovery about the epigenetic regulation of genes in gliomas, a type of brain cancer. The study found that the death receptor 4 (DR4) gene is frequently methylated in human astrocytic gliomas, leading to resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. This resistance is mediated by epigenetic silencing of DR4, making it a potential therapeutic target for glioma treatment.

Key Takeaways:

  • The study used methylation-sensitive BeadArray technology to identify novel epigenetically regulated genes associated with apoptosis and therapeutic targets in glioma therapy.
  • Death receptor 4 (DR4) is a cell surface protein that is targeted by TRAIL and is a potential therapeutic target for glioma treatment.
  • DR4 promoter methylation was detected in 60% of diffuse astrocytomas WHO grade 2, 75% of anaplastic astrocytomas WHO grade 3, and 70% of glioblastomas WHO grade 4.
  • Functional knockdown of DR4 by small interfering RNA in TRAIL-sensitive glioma cell line LN18 significantly mitigated apoptosis induced by an agonistic anti-DR4 antibody.
  • 5-Aza-2-deoxycytidine-mediated demethylation resulted in a functional reconstitution of DR4 on the cell surface of TRAIL-resistant glioma cell line U373 and sensitized U373 to TRAIL-mediated apoptosis.
  • The study concluded that DR4 promoter methylation is frequent in human astrocytic gliomas and epigenetic silencing of DR4 mediates resistance to TRAIL/DR4-based glioma therapies.

Statistics:

  • 60% of diffuse astrocytomas WHO grade 2 exhibited DR4 promoter hypermethylation.
  • 75% of anaplastic astrocytomas WHO grade 3 exhibited DR4 promoter hypermethylation.
  • 70% of glioblastomas WHO grade 4 exhibited DR4 promoter hypermethylation.
  • 5-Aza-2-deoxycytidine-mediated demethylation resulted in reconstitution of DR4 expression in glioma cell lines U373 and A172.
  • Functional knockdown of DR4 by small interfering RNA in LN18 significantly mitigated apoptosis induced by an agonistic anti-DR4 antibody.

Sources:

  • Elias, A. et al. (2009). Epigenetic Silencing of Death Receptor 4 Mediates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance in Gliomas. Clinical Cancer Research, 15(17), 5457-5465.
  • Gene Therapy Weekly editors (2009). Epigenetic Silencing of Death Receptor 4 Contributes to Resistance to TRAIL-Mediated Apoptosis in Gliomas. Gene Therapy Weekly.