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Cancer Res DOI:10.1158/0008-5472.CAN-17-0216

PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer.

Publication TypeJournal Article
Year of Publication2017
AuthorsHsu, 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
JournalCancer Res
Date Published2017 09 01
KeywordsAnimals, Bone Neoplasms, DNA Methylation, Gene Expression Regulation, Neoplastic, Mice, Mice, Knockout, Osteosarcoma, Protein Biosynthesis, Protein-Arginine N-Methyltransferases, Proteomics, Retinoblastoma Protein, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays

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. .


Alternate JournalCancer Res.
PubMed ID28655788
PubMed Central IDPMC5581676
Grant ListP01 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