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Inhibition of TGM2 enhances cisplatin sensitivity in MSH2-deficient bladder cancer

Wenjie Wei1,2, Xingyuan Xiao3, Chao Ren4

  • 1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cell Death Discovery
|May 28, 2026
PubMed

Insights

Loss of MSH2 gene impairs bladder cancer sensitivity to cisplatin. Combining cisplatin with a TGM2 inhibitor (GK921) shows promise for treating MSH2-deficient bladder cancer by restoring chemosensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The MSH2 gene is crucial for DNA mismatch repair and influences cancer prognosis.
  • Loss of MSH2 protein reduces bladder cancer sensitivity to cisplatin (CDDP).
  • A clinically applicable therapeutic strategy for MSH2-deficient bladder cancer is currently unavailable.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting TGM2 in MSH2-deficient bladder cancer.
  • To explore the mechanism by which MSH2 deficiency affects bladder cancer sensitivity to CDDP.

Main Methods:

  • MSH2 gene knockout in bladder cancer cells and mice.
  • Treatment with cisplatin (CDDP) and GK921 (TGM2 inhibitor).
  • Hi-C analysis to assess chromatin accessibility.
  • Analysis of transcription factor enrichment in the TGM2 promoter region.

Main Results:

  • MSH2 knockout reduced bladder cancer sensitivity to CDDP.
  • GK921 enhanced CDDP-induced tumor cell killing in MSH2-deficient bladder cancer and in Msh2-knockout mice.
  • MSH2 deficiency altered chromatin accessibility, increasing AP-1 transcription factor binding to the TGM2 promoter.
  • This led to increased TGM2 expression, mediating CDDP resistance.

Conclusions:

  • CDDP effectiveness in MSH2-deficient bladder cancer is dependent on TGM2 levels.
  • Combining CDDP with TGM2 inhibition is a potential therapeutic strategy for MSH2-deficient bladder cancer patients.

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