Methyltransferase MGMT upregulation drives metastasis by activating epithelial-mesenchymal transition in KRAS mutant colon cancer

Kirsten rat sarcoma (KRAS)-mutant colorectal cancer (CRC) is characterized by aggressive metastatic progression and profound therapeutic resistance. While direct inhibitors have emerged recently, their clinical application is often limited by rapid adaptive resistance, highlighting the urgent need to explore new therapeutic targets. 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 found that MGMT is upregulated in KRAS-mutant tumors and correlates with liver metastasis. Functionally, MGMT promotes epithelial-mesenchymal transition (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 epithelial-mesenchymal transition 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 MGMT as a multifaceted chromatin-modifying protein and establishes it as a promising therapeutic vulnerability to bypass resistance in KRAS-mutant CRC.