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

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 invasion. The combination of high expression of CSTF2 and high usage of RAC1 short-3'UTR isoform may be used as a powerful biomarker to predict poor prognosis in UCB. Our findings also suggest a CSTF2-regulated RAC1-3'UTR shortening program as an exploitable therapeutic strategy for patients with UCB.Significance: These findings demonstrate that the short isoform of RAC1 is critical in UCB tumorigenesis and may have implications for developing new therapeutic strategies to treat this disease. Cancer Res; 78(20); 5848-62. ©2018 AACR.

• Authors: Xin Chen, Jia-Xing Zhang, Jun-Hang Luo, Song Wu, Gang-Jun Yuan, Ning-Fang Ma, Yong Feng, Mu-Yan Cai, Ri-Xin Chen, Jun Lu, Li-Juan Jiang, Jie-Wei Chen, Xiao-Han Jin, Hai-Liang Liu, Wei Chen, Xin-Yuan Guan, Tie-Bang Kang, Fang-Jian Zhou, Dan Xie
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 20 Pg. 5848-5862 (10 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 30143523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• 3' Untranslated Regions
• CSTF2T protein, human
• Cleavage Stimulation Factor
• RAC1 protein, human
• RNA-Binding Proteins
• rac1 GTP-Binding Protein

Topics

• 3' Untranslated Regions
• Amino Acid Motifs
• Animals
• Carcinoma (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cleavage Stimulation Factor
• Computational Biology
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Prognosis
• RNA-Binding Proteins (genetics, metabolism)
• Sequence Analysis, RNA
• Treatment Outcome
• Urinary Bladder (pathology)
• Urinary Bladder Neoplasms (genetics, metabolism)
• Urothelium (pathology)
• Wound Healing
• rac1 GTP-Binding Protein (genetics)