Prmt1-mediated translation regulation is a crucial vulnerability of cancer

Through an shRNA screen we have identified Prmt1 as a genetic vulnerability of p53/Rb-null murine osteosarcoma cells. Depletion of Prmt1 in p53-deficient cells impairs tumor initiation and maintenance in vitro and in vivo. Mechanistic studies reveal that translation-associated pathways are enriched for Prmt1 downstream targets, implicating a role of Prmt1 in translation control. In particular, we have shown that loss of Prmt1 leads to a the decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. We also observed that p53/Rb-null cells are sensitive to p53-induced translation stress. Analysis of the human tumor cell Achilles data set further reveals that Prmt1 and translation-associated pathways converge on the same functional networks. We propose that targeted therapy directed to inhibition of Prmt1 and its associated translation-related pathways represents a novel and promising therapeutic strategy for p53-deficient cancer cells that exhibit dependencies on translation stress response. RNAs were extracted from Prmt1 control and conditional knockout murine osteosarcoma cell line. In each group, RNAs from cytoplasmic, light (<3 ribosomes) polysome fractions (termed Light), heavy (>3 ribosomes) polysome fractions (termed Heavy), as well as total cytoplasmic RNA (termed Total) were pooled and precipitated using Trizol-LS (Thermo Scientific). 500 ug of RNAs were used to prepare cDNA libraries using the illumina Truseq v2 kit. The libraries were quantified and sequenced using Illumina Nextseq sequencer.