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O-GlcNAcylation Regulation of SNAP29-Dependent Autophagy Activation Dictates Chemoresistance in Gastric Cancer

Liang Tang1, Shaoji Zhao1, Ziling Shao1

  • 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 23, 2026
PubMed

Insights

Low O-GlcNAc transferase (OGT) and O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) levels paradoxically promote chemoresistance in gastric cancer (GC). Enhancing O-GlcNAcylation sensitizes GC to chemotherapy, identifying OGT as a therapeutic target.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Chemoresistance to fluoropyrimidine and platinum agents is a major challenge in gastric cancer (GC).
  • The role of O-GlcNAc transferase (OGT) and O-GlcNAcylation in GC chemoresistance is not well understood.
  • OGT is often elevated in cancers, but its function in GC chemotherapy response is unclear.

Purpose of the Study:

  • To investigate the role of OGT and O-GlcNAcylation in GC chemoresistance.
  • To elucidate the molecular mechanisms underlying OGT's function in GC chemotherapy response.
  • To evaluate OGT as a potential therapeutic target for overcoming GC chemoresistance.

Main Methods:

  • Analysis of OGT expression and patient prognosis in GC.
  • In vitro and in vivo experiments involving OGT knockdown and O-GlcNAcylation inhibition.
  • Mechanistic studies using protein interaction assays, mass spectrometry, and molecular dynamics simulations.
  • Assessment of autophagy pathway modulation and response to chemotherapy agents (5-FU, OXA).
  • Evaluation of Thiamet-G as an O-GlcNAcylation enhancer in vivo.

Main Results:

  • Low OGT/O-GlcNAcylation levels correlate with resistance to 5-FU or oxaliplatin (OXA) in GC.
  • High OGT expression is associated with better prognosis in GC patients receiving fluoropyrimidine/platinum chemotherapy.
  • OGT inhibition or knockdown enhances chemoresistance, while OGT upregulation or O-GlcNAcylation enhancement sensitizes tumors to chemotherapy.
  • OGT O-GlcNAcylates SNAP29, inhibiting STX17-SNAP29-VAMP8 complex formation and autophagosome maturation.
  • Loss of SNAP29 O-GlcNAcylation promotes autophagy and chemoresistance.
  • Chemotherapy treatment downregulates OGT and O-GlcNAcylation, potentially creating a resistance loop.
  • Thiamet-G treatment sensitizes GC tumors to chemotherapy in vivo.

Conclusions:

  • The OGT/SNAP29 axis plays a context-dependent role in regulating GC chemoresistance through autophagy.
  • Low OGT/O-GlcNAcylation promotes chemoresistance by enhancing protective autophagy.
  • Targeting OGT or enhancing O-GlcNAcylation represents a promising strategy to overcome chemoresistance in gastric cancer.
Keywords:
5‐fluorouracilO‐GlcNAcylationSNAP29autophagychemoresistancegastric canceroxaliplatin

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