Alternative polyadenylation: An untapped source for prostate cancer biomarkers and therapeutic targets?

Asian Journal of Urology, 2021, 8 (4): 407-415 doi: 10.1016/j.ajur.2021.05.014

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Alternative polyadenylation: An untapped source for prostate cancer biomarkers and therapeutic targets?

Akira Kurozumi^a,Shawn E. Lupold^a,b,*(

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^a The James Buchanan Brady Urologic Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA
^b The Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

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Abstract

Objective: To review alternative polyadenylation (APA) as a mechanism of gene regulation and consider potential roles for APA in prostate cancer (PCa) biology and treatment.
Methods: An extensive review of mRNA polyadenylation, APA, and PCa literature was performed. This review article introduces APA and its association with human disease, outlines the mechanisms and components of APA, reviews APA in cancer biology, and considers whether APA may contribute to PCa progression and/or produce novel biomarkers and therapeutic targets for PCa.
Results: Eukaryotic mRNA 3′-end cleavage and polyadenylation play a critical role in gene expression. Most human genes encode more than one polyadenylation signal, and produce more than one transcript isoform, through APA. Polyadenylation can occur throughout the gene body to generate transcripts with differing 3′-termini and coding sequence. Differences in 3′-untranslated regions length can modify post-transcriptional gene regulation by microRNAs and RNA binding proteins, and alter mRNA stability, translation efficiency, and subcellular localization. Distinctive APA patterns are associated with human diseases, tissue origins, and changes in cellular proliferation rate and differentiation state. APA events may therefore generate unique mRNA biomarkers or therapeutic targets in certain cancer types or phenotypic states.
Conclusions: The full extent of cancer-associated and tissue-specific APA events have yet to be defined, and the mechanisms and functional consequences of APA in cancer remain incompletely understood. There is evidence that APA is active in PCa, and that it may be an untapped resource for PCa biomarkers or therapeutic targets.

Key words： Prostate cancer Polyadenylation Alternative polyadenylation 3′-untranslated region microRNA Intronic polyadenylation

Received: 10 November 2020 Available online: 20 October 2021

Corresponding Authors: Shawn E. Lupold E-mail: slupold@jhmi.edu

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Akira Kurozumi,Shawn E. Lupold. Alternative polyadenylation: An untapped source for prostate cancer biomarkers and therapeutic targets?[J]. Asian Journal of Urology, 2021, 8(4): 407-415.

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http://www.ajurology.com/EN/10.1016/j.ajur.2021.05.014 OR http://www.ajurology.com/EN/Y2021/V8/I4/407

Schematic of the cleavage and polyadenylation complex machinery assembled onto a pre-mRNA polyadenylation site. The CPA complex proteins consist of three major factors: The CPSF complex, the CSTF complex, and the cleavage factor complexes (CFIm and CFIIm), and other factors (Symplekin, PAP, and PABPN1). CPSFs consist of multiple protein subunits (CPSF30, CPSF73, CPSF100, CPSF160, hFip1, and WDR33) that collectively recognize and bind to the PAS specifically. CSTFs consist of three subunits (CSTF50, CSTF64, and CSTF77) that collectively recognize and bind to the GU-/U-rich elements downstream of the PAS. CFIms consist of three subunits (CFIm25, CFIm59, and CFIm68) that collectively recognize and bind to the U-rich elements upstream of the PAS. PAPs and PABPN1 are associated with the addition of untemplated adenosines. CFIIms (PCF11 and CLP1) contribute to transcription termination, and symplekin serves as a scaffold protein of CPA machinery. CPA, cleavage and polyadenylation; CPSF, cleavage and polyadenylation specificity factor; CSTF, cleavage stimulatory factor; PAS, polyadenylation signal; PABPN1, poly(A)-binding protein nuclear 1; PAPs, poly(A) polymerases.

Schematic of CR and UTR APA. APA can be classified as CR-APA and UTR-APA. CR-APA occurs when cleavage and polyadenylation takes place within the coding region or within coding region introns, resulting in truncated protein isoforms. U1snRNP recognizes and blocks early polyadenylation signals to prevent premature cleavage and polyadenylation. UTR-APA occurs when mRNAs encode more than one polyadenylation signal within the 3′-UTR. Proximal polyadenylation generates transcript isoforms with shorter 3′-UTRs and potentially fewer miRNA and RNA binding protein binding sites. Several factors, including NUDT21, CPSF6, and PABPN1 have been reported to inhibit proximal polyadenylation. APA, alternative polyadenylation; CR, coding region; UTR, untranslated region; RBP, RNA binding proteins; PAS, polyadenylation signal.

Alternative polyadenylation: An untapped source for prostate cancer biomarkers? Schematic to demonstrate shared relationships between APA and PCa progression. Carcinogenesis and cancer progression are associated with decreasing differentiation state and increasing cellular proliferation. Distal polyadenylation, IPA, and 3′-UTR shortening are similarly associated with proliferation, loss of differentiation, and cancer development. The mechanisms and relationships between APA and cancer remain incompletely defined. We hypothesize that these APA events could create unique transcript isoforms that could serve as diagnostic or prognostic biomarkers for prostate cancer and other urologic malignancies. APA, alternative polyadenylation; IPA, intronic polyadenylation; PCa, prostate cancer; UTR, untranslated region.

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