{
  "abstract": "Background Oxaliplatin resistance is a major obstacle in colorectal cancer (CRC) treatment. While aberrant DNA methylation contributes to chemoresistance, the upstream regulatory mechanisms remain unclear. This study investigates how the TRPM7-M7CK axis modulates UHRF1 phosphorylation to drive DNA hypermethylation, senescence escape, and oxaliplatin resistance in CRC.Methods Oxaliplatin-resistant CRC cells (HCT116-OR, SW480-OR) were established via concentration escalation. DNA methylation was assessed by dot blot and ChIP-qPCR. Protein interactions were analyzed by Co-IP, immunofluorescence, and BiFC. The kinase-substrate relationship was validated by mutagenesis and phospho-specific antibodies. A small-molecule inhibitor targeting M7CK was identified through virtual screening and validated by SPR. In vivo efficacy was evaluated in subcutaneous xenograft models.Results Resistant cells exhibited global DNA hypermethylation with specific enrichment of DNMT1 at senescence-related tumor suppressor gene promoters (CDKN1A, CDKN2A). UHRF1 interacted with DNMT1 via its SRA domain, and this interaction was significantly enhanced in resistant cells. Under chemotherapeutic stress, TRPM7 underwent caspase-dependent cleavage, releasing the M7CK kinase fragment which translocated to the nucleus and directly bound UHRF1’s SRA domain. M7CK phosphorylated UHRF1 at Ser500, potentiating UHRF1-DNMT1 complex assembly and driving promoter hypermethylation of CDKN1A/CDKN2A, leading to senescence escape. Pharmacological targeting of M7CK with MK-1602 (a novel inhibitor identified by virtual screening, KD = 6.49 μM by SPR) disrupted M7CK-UHRF1 binding, reversed DNA hypermethylation, reactivated senescence programs, and synergized with oxaliplatin to suppress tumor growth in vivo. The proposed mechanism is summarized in Figure 1 ( IDDF2026-ABS-0299 Figure 1. Schematic illustration of the TRPM7-M7CKUHRF1DNMT1 axis in oxaliplatin resistant colorectal cancer).Conclusions This study unveils a novel signaling cascade wherein TRPM7 cleavage generates M7CK, which phosphorylates UHRF1 at Ser500 to enhance DNMT1 recruitment, driving epigenetic silencing of senescence genes and oxaliplatin resistance. Targeting this axis with MK-1602 represents a promising therapeutic strategy to overcome chemoresistance in CRC.Abstract IDDF2026-ABS-0299 Figure 1",
  "authors": [
    {
      "affiliations": [
        "Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China"
      ],
      "name": "Fangyuan Zhou"
    },
    {
      "affiliations": [
        "Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China"
      ],
      "name": "Shenglan Yang"
    }
  ],
  "title": "IDDF2026-ABS-0299 TRPM7/M7CK-UHRF1 axis drives dna methylation-mediated senescence escape to promote oxaliplatin resistance in colorectal cancer",
  "uid": "4da2728a-669d-5db6-83ad-fd83c0028f75"
}