The 3′ UTR Landscape in Cancer

Abstract

Oncogenesis is tightly connected with dysregulated gene expression. Alterations occur at many levels, including in posttranscriptional regulatory elements that control the stability, cellular localisation or translation efficiency of messenger ribonucleic acids (mRNAs). These elements are located primarily in the 3′ untranslated region (UTR) of mRNAs. Multiple examples are known of oncogenes whose activity and function become altered owing to changes in their 3′ UTRs. Strikingly, recent studies have uncovered global changes of 3′ UTRs in cancers, going beyond individual genes. Cancer cells express transcripts with systematically shorter 3′ UTRs compared to normal cells. The implications of these changes for cellular biology are poorly understood, but high‐throughput approaches are being developed to uncover the regulators, targets and impact of 3′ UTR‐based regulation. The hope is that a renewed understanding of 3′ UTR alterations can open new therapeutic opportunities.

Key Concepts

  • The maturation of most messenger RNAs includes 3′ end cleavage followed by the addition of a polyadenosine tail.
  • Most human protein‐coding genes express multiple isoforms, which can differ, among others, in their 3′ untranslated regions (3′ UTRs).
  • In proliferating cells, including cancer cells, cleavage and polyadenylation tend to occur at coding region proximal sites, giving rise to isoforms with short 3′ UTRs.
  • As 3′ UTRs contain binding sites for many RNA‐binding regulatory proteins, it is likely that short 3′ UTR isoforms are less susceptible to posttranscriptional regulation.
  • A role of 3′ UTR length changes in the progression and prognosis of cancers has been proposed.

Keywords: polyadenylation; 3′ UTR; cancer; mRNA processing; gene regulation

Figure 1. Sequence elements involved in mRNA 3′‐end processing. (a) The relative frequency of poly(A) signals in the transcriptome correlates with their in vitro efficiency in guiding 3′ end polyadenylation (Sheets et al., ). (b) Canonical architecture of an mRNA 3′ end with an upstream sequence element (USE, often UGUA), the poly(A) signal, the cleavage site (often, cleavage occurs within a CA dinucleotide) and degenerate, UG‐rich downstream sequence elements (DSE). (c) The frequency of canonical poly(A) signals increases towards the end of terminal exons. Individual terminal exons were divided into 10 bins and in each bin, the frequency of the canonical AAUAAA signal among all occurrences of poly(A) signals within 60 nt upstream of annotated poly(A) sites was determined.
Figure 2. Consequences of alternative polyadenylation. The upper part of the figure shows a schematic representation of a gene from which alternative polyadenylation gives rise to two isoforms, differing only in their 3′ UTR length. The long 3′ UTR isoform can interact with a variety of factors, RBPs, miRNAs and lncRNAs, these interactions modulating the stability, export and subcellular location of the mRNA and the encoded protein.
Figure 3. Principle used to detect changes in poly(A) site usage between samples based on read coverages from RNAseq libraries. Read coverages across the gene body of DICER1 (and its terminal exon in the zoomed bottom panel) from control cells and cells that were treated with siRNA against NUDT21. In the knockdown sample, the predominant usage of a proximal poly(A) site leads to markedly reduced coverage further downstream.
Figure 4. Perturbations in 3′‐end processing in cancers. (a) For TCGA cancer types with at least five available pairs of matched tumour‐normal tissue samples, the differences in 3′ UTR length across sample pairs are shown. Each dot represents the median change in 3′ UTR length over all genes with multiple used PAS in the tumour compared to the normal sample. Horizontal lines indicate, for every cancer type, the median change in 3′ UTR length among all patients from the corresponding cancer cohort. (b) On the basis of matched tumour‐normal sample pairs, we computed the ratio between the expression levels (in fragments per kilobase of transcripts per million, FPKM) of 3′ end processing factors in the tumour and normal samples. The median ratio for each cancer type and each factor is shown. Red indicates a higher median expression in tumour, while blue indicates higher expression in the normal tissue samples. The cancer types that are covered are as follows: STAD, stomach adenocarcinoma; READ, rectum adenocarcinoma; KIRC, kidney renal clear cell carcinoma; KICH, kidney chromophobe; THCA, thyroid carcinoma; LIHC, liver hepatocellular carcinoma; PRAD, prostate adenocarcinoma; KIRP, kidney renal papillary cell carcinoma; COAD, colon adenocarcinoma; ESCA, oesophageal carcinoma; HNSC, head and neck squamous cell carcinoma; BRCA, breast invasive carcinoma; BLCA, bladder urothelial carcinoma; UCEC, uterine corpus endometrial carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma.
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Further Reading

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Schmidt, Ralf, Ghosh, Souvik, and Zavolan, Mihaela(Jun 2018) The 3′ UTR Landscape in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027958]