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 main...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-09, Vol.77 (17), p.4613-4625
Main Authors: Hsu, Jessie Hao-Ru, Hubbell-Engler, Benjamin, Adelmant, Guillaume, Huang, Jialiang, Joyce, Cailin E, Vazquez, Francisca, Weir, Barbara A, Montgomery, Philip, Tsherniak, Aviad, Giacomelli, Andrew O, Perry, Jennifer A, Trowbridge, Jennifer, Fujiwara, Yuko, Cowley, Glenn S, Xie, Huafeng, Kim, Woojin, Novina, Carl D, Hahn, William C, Marto, Jarrod A, Orkin, Stuart H
Format: Article
Language:English
Subjects:
Animals
Arginine
Bone cancer
Bone Neoplasms - genetics
Bone Neoplasms - metabolism
Bone Neoplasms - pathology
Cancer
Cellular stress response
DNA Methylation
Gene Expression Regulation, Neoplastic
Initiation complex
Methylation
Mice
Mice, Knockout
Null cells
Osteosarcoma - genetics
Osteosarcoma - metabolism
Osteosarcoma - pathology
p53 Protein
Protein arginine methyltransferase
Protein Biosynthesis
Protein-Arginine N-Methyltransferases - physiology
Proteomics
Retinoblastoma Protein - physiology
Sarcoma
Translation
Translation initiation
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - physiology
Xenograft Model Antitumor Assays
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Summary: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. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-17-0216