PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer.
Through an shRNA screen, we identified the protein arginine methyltransferase Prmt1 as a vulnerable intervention point in murine p53/Rb-null osteosarcomas, the human counterpart of which lacks effective therapeutic options. Depletion of Prmt1 in p53-deficient cells impaired tumor initiation and maintenance and Mechanistic studies reveal that translation-associated pathways were enriched for Prmt1 downstream targets, implicating Prmt1 in translation control. In particular, loss of Prmt1 led to a decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. p53/Rb-null cells were sensitive to p53-induced translation stress, and analysis of human cancer cell line data from Project Achilles further revealed that Prmt1 and translation-associated pathways converged on the same functional networks. We propose that targeted therapy against Prmt1 and its associated translation-related pathways offer a mechanistic rationale for treatment of osteosarcomas and other cancers that exhibit dependencies on translation stress response. .
|Year of Publication
2017 09 01
|PubMed Central ID
P01 CA203655 / CA / NCI NIH HHS / United States
U01 CA105423 / CA / NCI NIH HHS / United States
U01 CA199253 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
U01 CA176058 / CA / NCI NIH HHS / United States