Alternative polyadenylation is a determinant of oncogenic Ras function.

Abstract

Alternative polyadenylation of mRNA has important but poorly understood roles in development and cancer. Activating mutations in the Ras oncogene are common drivers of many human cancers. From a screen for enhancers of activated Ras (<i>let-60</i>) in <i>Caenorhabditis elegans</i>, we identified <i>cfim-1</i>, a subunit of the alternative polyadenylation machinery. Ablation of <i>cfim-1</i> increased penetrance of the multivulva phenotype in <i>let-60/Ras</i> gain-of-function (gf) mutants. Depletion of the human <i>cfim-1</i> ortholog <i>CFIm25</i>/<i>NUDT21</i> in cancer cells with KRAS mutations increased their migration and stimulated an epithelial-to-mesenchymal transition. <i>CFIm25</i>-depleted cells and <i>cfim-1</i> mutants displayed biased placement of poly(A) tails to more proximal sites in many conserved transcripts. Functional analysis of these transcripts identified the multidrug resistance protein <i>mrp-5/ABCC1</i> as a previously unidentified regulator of <i>C. elegans</i> vulva development and cell migration in human cells through alternative 3′UTR usage. Our observations demonstrate a conserved functional role for alternative polyadenylation in oncogenic Ras function.