Methyltransferase MGMT Upregulation Drives Metastasis by Activating Epithelial-Mesenchymal Transition in KRAS Mutant Colon Cancer

Kirsten rat sarcoma (KRAS)-mutant colorectal cancer (CRC) is associated with metastatic progression and therapeutic resistance, yet the epigenetic mechanisms driving these phenotypes remain incompletely understood. Here, we identify O6-methylguanine-DNA methyltransferase (MGMT), a classical DNA repair enzyme, as a novel epigenetic facilitator of metastasis in KRAS-mutant CRC. Through integrated analyses of clinical cohorts and orthotopic metastasis models, we identify that MGMT is upregulated in KRAS-mutant tumors and correlates with liver metastasis. Functionally, MGMT promotes EMT and enhances metastatic capacity in vivo and in vitro. Mechanistically, we unveil a non-canonical function of MGMT in CRC: it interacts with histone H3 and reduces repressive H3K9me3 marks at the promoter of the EMT master regulator TWIST1, thereby activating its transcription. Importantly, we demonstrate that targeting MGMT sensitizes KRAS-mutant colorectal cancer to anti-EGFR therapy in preclinical models, providing a novel combinatorial strategy for this recalcitrant cancer subtype. Our study redefines the role of MGMT as a chromatin-modifying protein and proposes it as a promising therapeutic target in KRAS-mutant CRC.