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RRM1 O-GlcNAcylation inhibition suppresses pancreatic cancer via TK1-mediated replication stress

Sui-Chih Tien1, Mei Shih1, Chun-Mei Hu2

  • 1Genomics Research Center, Academia Sinica, Taipei, 115201, Taiwan.

Cancer Gene Therapy
|March 29, 2025
PubMed

Insights

Modifying O-GlcNAcylation of ribonucleotide reductase (RRM1) impacts pancreatic cancer cell growth and DNA damage. Reduced RRM1 O-GlcNAcylation sensitizes cancer cells to gemcitabine, suggesting a new therapeutic approach.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • O-GlcNAcylation of ribonucleotide reductase large subunit M1 (RRM1) at T734 affects genomic instability and cell transformation.
  • The role of RRM1 O-GlcNAcylation in pancreatic cancer progression is not well understood.

Purpose of the Study:

  • To investigate the impact of RRM1 O-GlcNAcylation on pancreatic cancer progression.
  • To explore the therapeutic potential of modulating RRM1 O-GlcNAcylation.

Main Methods:

  • CRISPR knock-in technology to create RRM1-T734A mutation in PANC-1 cells.
  • Analysis of replication stress, DNA damage, S-phase progression, and cell growth.
  • Investigation of RRM1 interactions with RRM2 and RRM2B, and nucleotide levels.
  • Assessment of thymidine kinase 1 (TK1) stabilization and gemcitabine sensitivity.

Main Results:

  • The RRM1-T734A mutation heightened replication stress-induced DNA damage and S-phase delays.
  • This mutation diminished in vitro tumor cell growth by altering RRM1 interactions, decreasing NTPs, and disrupting dNTP equilibrium.
  • Increased dTTP levels via TK1 stabilization led to S-phase delay, which was reversed by TK1 silencing.
  • Reduced RRM1 O-GlcNAcylation increased pancreatic cancer cell sensitivity to gemcitabine.

Conclusions:

  • O-GlcNAcylation of RRM1 at T734 is crucial for maintaining genomic stability and promoting pancreatic cancer malignancy.
  • Targeting RRM1 O-GlcNAcylation represents a potential therapeutic strategy for pancreatic cancer, enhancing gemcitabine efficacy.

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