CFIm25 links Alternative Polyadenylation to Glioblastoma Tumor Suppression

The global shortening of mRNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression(1,2). The 3′UTR truncation of growth promoting mRNA transcripts that relieves intrinsic microRNA- and AU-rich element-mediated repression has been observed to correlate with cellular transformation(3); however, the importance to tumorigenicity of RNA 3′ end processing factors that potentially govern APA is unknown. Here, we have identified CFIm25 as a broad repressor of proximal poly(A) site usage that, when depleted, increases cell proliferation. Applying a regression model on standard RNA-seq data for novel APA events, we identified at least 1,450 genes with shortened 3′UTRs after CFIm25 knockdown, representing 11% of significantly expressed mRNA in HeLa cells. Dramatic increases in expression of several known oncogenes including Cyclin D1 are observed as a consequence of CFIm25 depletion. Importantly, we identified a subset of CFIm25-regulated APA genes with shortened 3′UTRs in glioblastoma (GBM) tumors that have reduced CFIm25 expression. Downregulation of CFIm25 expression in glioblastoma cells enhances their tumorigenic properties and increases tumor size while CFIm25 overexpression reduces these properties and inhibits tumor growth. These findings identify a pivotal role of the CFIm25 in governing APA and reveal a previously unknown connection between CFIm25 and glioblastoma tumorigenicity.