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Oncogenic Ras suppresses ING4-TDG-Fas axis to promote apoptosis resistance

Jie Sun1, Qi Shen2, Haiqi Lu2

  • 1Laboratory of Cancer Biology, Provincial Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.

Oncotarget
|November 7, 2015
PubMed

Insights

Ras activation in cancer suppresses thymine-DNA glycosylase (TDG) by inhibiting ING4. Restoring TDG reactivates Fas, restoring apoptosis sensitivity and suppressing pancreatic cancer growth.

Area of Science:

  • Molecular oncology
  • Epigenetics
  • Cancer biology

Background:

  • Aberrant Ras activation is common in many cancers.
  • DNA demethylation is crucial for cancer development.
  • The role of Ras in regulating DNA demethylation during carcinogenesis was unclear.

Purpose of the Study:

  • To investigate the mechanism by which Ras regulates DNA demethylation in cancer.
  • To explore the role of thymine-DNA glycosylase (TDG) in Ras-driven carcinogenesis.

Main Methods:

  • Investigated Ras's effect on TDG expression and activity.
  • Analyzed the interaction between ING4, TDG, and the TDG promoter.
  • Examined TDG's role in recruiting JMJD3 to the Fas promoter.
  • Assessed the impact of TDG on Fas expression and apoptosis sensitivity.
  • Evaluated TDG's effect on xenograft pancreatic cancer tumorigenicity.

Main Results:

  • Ras was found to downregulate thymine-DNA glycosylase (TDG).
  • Ras inhibited the interaction between transcription activator ING4 and the TDG promoter.
  • TDG recruited histone lysine demethylase JMJD3 to the Fas promoter, activating its expression.
  • TDG restored sensitivity to apoptosis and suppressed in vivo tumorigenicity of xenograft pancreatic cancer.

Conclusions:

  • Ras-mediated inhibition of ING4 suppresses TDG expression.
  • Restoring TDG function can reactivate Fas expression and apoptosis.
  • Targeting the Ras-ING4-TDG-Fas pathway may offer a therapeutic strategy for Ras-driven cancers.
Keywords:
ING4RasTDGoncogenesis

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