|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Hsu, JHao-Ru, 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|
|Date Published||2017 Jun 27|
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.
|Alternate Journal||Cancer Res.|
|Grant List||U01 CA176058 / CA / NCI NIH HHS / United States|