Prmt1-mediated translation regulation is a crucial vulnerability of cancer.

Jessie Hao-Ru Hsu
Benjamin Hubbell-Engler
Guillaume Adelmant
Jialiang Huang
Cailin E Joyce
Francisca Vazquez
Barbara A Weir
Philip Montgomery
Aviad Tsherniak
Andrew O Giacomelli
Jennifer A Perry
Jennifer J. Trowbridge, The Jackson Laboratory
Yuko Fujiwara
Glenn S Cowley
Huafeng Xie
Woojin Kim
Carl D Novina
William C Hahn
Jarrod A Marto
Stuart H Orkin


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 in vitro and in vivo 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.