Alternative polyadenylation is a determinant of oncogenic Ras function

Alternative polyadenylation of pre-mRNA has been recently shown to play important roles in development and cancer. Activating mutations in the Ras oncogene are common drivers of many human cancers but the mechanisms by which they cooperate with alternative polyadenylation are not known. By exploiting the genetics ofC. elegans, we identifiedcfim-1/CFIm25, a subunit of the alternative polyadenylation machine, as a key determinant of hyperactive Ras function. Ablation ofcfim-1increased penetrance of multivulva phenotype inlet-60/Rasgain-of-function (gf) mutant through shortening of transcripts at the 3’ untranslated region, including p21 activated kinasepak-1/PAK1and multidrug transportermrp-5/ABCC1. Depletion of CFIm25 in human KRAS-driven cancer cells resulted in a similar shortening of 3’ untranslated regions in thePAK1andABCC1transcripts, which caused an epithelial-to-mesenchymal transition and increased cell migration. Exploiting the mechanisms by which alternative polyadenylation affects activated oncogene output could offer novel approaches for the treatment of Ras-driven tumors.