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Cancer Res. 2017 Sep 1;77(17):4613-4625. doi: 10.1158/0008-5472.CAN-17-0216. Epub 2017 Jun 27.

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

Author information

1
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts.
2
Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts.
4
Department of Cancer Immunology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
7
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, Maine.
8
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts. Stuart_Orkin@dfci.harvard.edu.
9
Howard Hughes Medical Institute, Boston, Massachusetts.

Abstract

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. Cancer Res; 77(17); 4613-25. ©2017 AACR.

PMID:
28655788
PMCID:
PMC5581676
DOI:
10.1158/0008-5472.CAN-17-0216
[Indexed for MEDLINE]
Free PMC Article

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