CSTF2-Induced Shortening of the RAC1 3'UTR Promotes the Pathogenesis of Urothelial Carcinoma of the Bladder

Cancer Research
Xin ChenDan Xie

Abstract

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 RAC1 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 RAC1 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 RAC1 in UCB by mediating slow transcriptional elongation at RAC1 Cotranscriptional recruitment of CSTF2 on the GUAAU motif at proximal polyadenylation site of RAC1 attenuated the recruitment of two transcription factors AFF1 and AFF4, causing the defects in elongation. CSTF2 regulated the tumorigenic functions of the shorter RAC1 isoform in UCB cells, enhancing cell proliferation, migration, and i...Continue Reading

Citations

Feb 23, 2020·Cancers·Rashidah BaharudinNurul Syakima Ab Mutalib
Aug 1, 2019·International Journal of Oncology·Yuenan LiuXiaoping Zhang
Apr 28, 2019·Cells·Pradip DeNandini Dey
Oct 11, 2020·Molecular Cancer Research : MCR·Xiaonan WangZhengsheng Wu
Jul 2, 2021·Frontiers in Cell and Developmental Biology·Chuan HuYongming Xi

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