Lengthening of 3′ Untranslated Regions of mRNAs by Alternative Polyadenylation Is Associated With Tumor Progression and Poor Prognosis of Clear Cell Renal Cell Carcinoma

Abstract

Alternative polyadenylation (APA) is emerging as a major posttranscriptional mechanism for gene regulation in cancer. A prevailing hypothesis is that shortening of the 3′ untranslated region (3′UTR) increases oncoprotein expression because of the loss of miRNA-binding sites (MBSs). We showed that the longer 3′UTR is associated with a more advanced tumor stage in patients with clear cell renal cell carcinoma (ccRCC). More surprisingly, 3′UTR shortening is correlated with better overall survival in patients with ccRCC. Furthermore, we identified a mechanism by which longer transcripts lead to increased oncogenic protein and decreased tumor-suppressive protein expression compared to the shorter transcripts. In our model, shortening of 3′UTRs by APA may increase the mRNA stability of the majority of the potential tumor-suppressor genes due to the loss of MBSs and AU-rich elements (AREs). Unlike potential tumor-suppressor genes, the potential oncogenes display much lower MBS and ARE density and globally much higher m6A density in distal 3′UTRs. As a result, 3′UTRs shortening decreases the mRNA stability of potential oncogenes and enhances the mRNA stability of potential tumor-suppressor genes. Our findings highlight the cancer-specific pattern of APA regulation and extend our understanding of the mechanism of APA-mediated 3′UTR length changes in cancer biology.