WNT-driven PRMT1 Nuclear Localization Generates Synthetic Lethality in Colorectal Cancers

Colorectal cancer (CRC) arises from multi-step accumulation of genetic and epigenetic mutations that deregulate intestinal homeostasis leading to neoplastic transformation and metastases. Constitutive activation of WNT signaling is considered the initial driver oncogenic event to which CRCs remain addicted, also in their most aggressive metastatic forms. WNT activation provokes an aberrant signaling that converges into the nucleus where transcription and chromatin-remodeling factors cooperate to regulate cell identity. This leads to deregulated proliferation, block of differentiation and evasion from cell death pathways. We found that the protein arginine methyltransferase 1 (PRMT1) is synthetic lethal with WNT oncogenic activation in both genetically-defined mouse models and patient-derived metastatic CRC organoids.  WNT activation regulates the subcellular localization of PRMT1, inducing its complete nuclear translocation. This makes CRCs specifically dependent on PRMT1 enzymatic activity to sustain WNT-dependent proliferation regardless of the mutational landscape carried by distinct patients. Together these data uncover a new molecular crosstalk between WNT activation and PRMT1 activity and place PRMT1 inhibition as a potential strategy to counteract CRC addiction to WNT oncogenic activation.