CFIm25 links alternative polyadenylation to glioblastoma tumour suppression

Abstract

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 expression1,2. 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 transformation3; 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.

The interplay between lnRNAs, SNPs, and protein complexes - what does it mean for cancer metabolism?

“…However, a recent report introduced CFIm25 as a tumor suppressor in glioblastoma, negatively regulating the expression of GLS via 3UTR processing. 9 Although it may initially seem contradictory to our findings, it has been reported that CCAT2 is not expressed in glioblastoma cell lines. This suggests that interaction with the lncRNA may modulate the function of the protein in a cell-specific way.…”

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

“…To determine whether reduced U1 snRNA levels in our snRNP biogenesis mutants correlated with expression of shorter mRNAs, mapped RNA-seq reads were analyzed using the DaPars linear regression algorithm (Masamha et al 2014;Xia et al 2014). DaPars output is displayed as a percentage of distal poly(A) site usage index (PDUI) for each transcript, or as the difference in the PDUI value between wild-type and mutant (ΔPDUI).…”

Alternative polyadenylation and RNA-binding proteins

“…Altered expressions of CPSF and CFIm complex members have also been implicated in the selection of alternate poly(A) signals in normal physiological settings including self-renewal of embryonic stem cells and in disease states (reviewed in Zheng & Tian 2014). For example, decreased CFIm25 expression correlated with 3′-UTR shortening events in glioblastoma patients (Masamha et al 2014). Furthermore, a combinatorial approach of computation and experimentation revealed a pattern of 3′-UTR length changes in breast cancer patients/cells and a potential link between APA, CSTF2, and EGF (epidermal growth factor) signaling (Akman et al 2015).…”