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

MSH2 (mutS homolog 2) gene, a key component of the DNA mismatch repair system, garners significant attention for its influence on cancer progression and prognosis. Loss of MSH2 protein decreases the chemosensitivity of bladder cancer (BCa) to cisplatin (CDDP). However, precision therapeutic strategy based on MSH2 deficiency is not available clinically. Herein, we reported that knockout of MSH2 reduced the sensitivity of BCa to CDDP. Importantly, GK921, a TGM2-specific inhibitor, increased tumor cell killing by CDDP in MSH2-deficient BCa. GK921 also promoted the chemotherapeutic sensitivity of Msh2-knockout mice to CDDP. In addition, Hi-C analysis indicated that MSH2 deficiency rewired chromatin accessibility of the TGM2 promoter region, leading to recruit more transcription factors. Accordingly, we found that the enrichment levels of transcription factor AP-1 in TGM2 promoter region were increased in MSH2-knockout BCa cells, thereby promoting the expression of TGM2 transcriptionally. This study uncovers that CDDP effectiveness depends on TGM2 levels in MSH2-deficient BCa and that the combination of CDDP with TGM2 inhibition may represent a promising therapeutic strategy for MSH2-deficient BCa patients.