PRMT1-Mediated Translation Regulation is a Crucial Vulnerability of Cancer

Image of Osteosarcoma in a human bone
Hsu JH, Hubbell-Engler B, Adelmant G, Huang J, Joyce CE, Vazquez F, Weir BA, Montgomery P, Tsherniak A, Giacomelli AO, Perry JA, Trowbridge J, Fujiwara Y, Cowley GS, Xie H, Kim W, Novina CD, Hahn WC, Marto JA, Orkin SH

Cancer Research

June 27, 2017

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. 

Type of Publication: 
Primary
Program:
CTD²
Last updated: August 25, 2017