Title

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

Document Type

Article

Publication Date

9-1-2017

JAX Source

Cancer Res 2017 Sep 1; 77(17):4613-4625

Volume

77

Issue

17

First Page

4613

Last Page

4625

ISSN

1538-7445

PMID

28655788

DOI

https://doi.org/10.1158/0008-5472.CAN-17-0216

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.

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