CSTF2-Induced Shortening of the 3'UTR Promotes the Pathogenesis of Urothelial Carcinoma of the Bladder.

Shortening of the 3' untranslated regions (3'UTR) of mRNA is an important mechanism for oncogene activation. However, 3'UTR alteration events, their pathologic functions, and underlying mechanisms in human urothelial carcinoma of the bladder (UCB) are not clear. Here, we combine RNA sequencing, bioinformatics, and clinical studies in two independent cohorts of patients with UCB to identify a novel shorter 3'UTR isoform that is frequently expressed in UCB and is critical in the tumorigenesis and acquisition of a poor prognostic phenotype in patients. Short 3'UTR isoform of substantially upregulated RAC1 expression by escaping from miRNA-targeted repression and played an essential oncogenic role in UCB pathogenesis. An important cleavage/polyadenylation factor, cleavage stimulation factor 2 (CSTF2), induced 3'UTR shortening of in UCB by mediating slow transcriptional elongation at Cotranscriptional recruitment of CSTF2 on the GUAAU motif at proximal polyadenylation site of attenuated the recruitment of two transcription factors AFF1 and AFF4, causing the defects in elongation. CSTF2 regulated the tumorigenic functions of the shorter isoform in UCB cells, enhancing cell proliferation, migration, and invasion. The combination of high expression of CSTF2 and high usage of short-3'UTR isoform may be used as a powerful biomarker to predict poor prognosis in UCB. Our findings also suggest a CSTF2-regulated -3'UTR shortening program as an exploitable therapeutic strategy for patients with UCB. These findings demonstrate that the short isoform of is critical in UCB tumorigenesis and may have implications for developing new therapeutic strategies to treat this disease. .