Alternative Polyadenylation Patterns for Novel Gene Discovery and Classification in Cancer

Begik, Oguzhan; Oyken, Merve; Alican, Tuna Cinkilli; Can, Tolga; Erson-Bensan, Ayşe Elif

doi:10.1016/j.neo.2017.04.008

Cited by 15 publications

(13 citation statements)

References 31 publications

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“…It has become increasingly evident that APA plays crucial roles in both normal development and in diseases including cancer 9, 10. The effect of APA on cancer transcriptomes may be cancer type specific, but this remains to be further investigated 11.…”

Section: Introductionmentioning

confidence: 99%

NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation

et al. 2019

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Purpose: Nudix Hydrolase 21 (NUDT21) is a crucial mediator involved in alternative polyadenylation (APA), and this molecule has been reported to be a tumor suppressor in human cancers. However, neither the role NUDT21 plays in bladder cancer (BC) nor the mechanisms which are involved have been investigated.Methods: Expression levels of NUDT21 in BC were evaluated with real-time PCR, western blotting, and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the function of NUDT21 in tumorigenesis in bladder cancer cells. The TOP/FOP flash reporter assay, western blot, and global APA site profiling analysis were used to identify the pathway which mediates the biologic roles of NUDT21 in BC.Results: NUDT21 expression is reduced in BC tissue and cells, and BC patients with lower NUDT21 expression have shorter overall and recurrent-free survival than patients with higher NUDT21 expression. NUDT21 ectopic expression or knockdown respectively profoundly inhibited or promoted the capacity of BC cells for proliferation, migration and invasion. We also identified a number of genes with shortened 3'UTRs through modulation of NUDT21 expression, and further characterized the NUDT21-regulated genes ANXA2 and LIMK2. We found NUDT21 modulates the expression of ANXA2 and LIMK2 in the Wnt/β-catenin and NF-κB signaling pathways.Conclusions: These findings show NUDT21 plays a crucial role in BC progression, at least in part through ANXA2 and LIMK2 which act by alternative polyadenylation. NUDT21 may thus have potential as a diagnostic and therapeutic target in treatment of BC.

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Section: Introductionmentioning

confidence: 99%

NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation

et al. 2019

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“…The usage of shorter 3’UTRs via APA events is most common (91%) in cancer and occurs on a global scale [4]. There has been an increase in the trial to systematically detect APA events across diverse cancers including breast cancer [3, 5]. Especially, APA usages in specific genes and transcriptional signalings, such as PRELID1 [6], USP9X, SNX3, and YME1L1D [7], have been reported as a strong predictor of clinical outcomes in the breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Alternative polyadenylation of single cells delineates cell types and serves as a prognostic marker in early stage breast cancer

et al. 2019

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Alternative polyadenylation (APA) in 3’ untranslated regions (3’ UTR) plays an important role in regulating transcript abundance, localization, and interaction with microRNAs. Length-variation of 3’UTRs by APA contributes to efficient proliferation of cancer cells. In this study, we investigated APA in single cancer cells and tumor microenvironment cells to understand the physiological implication of APA in different cell types. We analyzed APA patterns and the expression level of genes from the 515 single-cell RNA sequencing (scRNA-seq) dataset from 11 breast cancer patients. Although the overall 3’UTR length of individual genes was distributed equally in tumor and non-tumor cells, we found a differential pattern of polyadenylation in gene sets between tumor and non-tumor cells. In addition, we found a differential pattern of APA across tumor types using scRNA-seq data from 3 glioblastoma patients and 1 renal cell carcinoma patients. In detail, 1,176 gene sets and 53 genes showed the distinct pattern of 3’UTR shortening and over-expression as signatures for five cell types including B lymphocytes, T lymphocytes, myeloid cells, stromal cells, and breast cancer cells. Functional categories of gene sets for cellular proliferation demonstrated concordant regulation of APA and gene expression specific to cell types. The expression of APA genes in breast cancer was significantly correlated with the clinical outcome of earlier stage breast cancer patients. We identified cell type-specific APA in single cells, which allows the identification of cell types based on 3’UTR length variation in combination with gene expression. Specifically, an immune-specific APA signature in breast cancer could be utilized as a prognostic marker of early stage breast cancer.

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“…miRNA regulation is highly dependent upon the availability of binding sites within the 3′ UTR of the IMP1 transcript (13). Loss of miRNA regulation via shortening of the 3′ UTR through APA confers altered mRNA stability and protein expression and is often associated with more aggressive tumors in a number of solid tumor cancers, including CRC (14)(15)(16)(17). Studies in fibroblasts suggest that shortening of the IMP1 3′ UTR confers enhanced colony formation (13); however, to the best of our knowledge, our study provides the first in vivo evidence that IMP1 3′ UTR shortening enhances CRC metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…APA affects RNA stability, localization, translation rate and secondary structure (14). Usage of the proximal polyA site or 3′ UTR shortening occurs in a number of solid tumors and can influence protein expression levels by altering transcript stability and conformation (15). Shorter 3′ UTRs are associated with aggressive tumors in breast, lung (16) and colon (17).…”

Section: Introductionmentioning

confidence: 99%

IMP1 3′ UTR shortening enhances metastatic burden in colorectal cancer

et al. 2018

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The RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) is overexpressed in colorectal cancer (CRC); however, evidence for a direct role for IMP1 in CRC metastasis is lacking. IMP1 is regulated by let-7 microRNA, which binds in the 3′ untranslated region (UTR) of the transcript. The availability of binding sites is in part controlled by alternative polyadenylation, which determines 3′ UTR length. Expression of the short 3′ UTR transcript (lacking all microRNA sites) results in higher protein levels and is correlated with increased proliferation. We used in vitro and in vivo model systems to test the hypothesis that the short 3′ UTR isoform of IMP1 promotes CRC metastasis. Herein we demonstrate that 3′ UTR shortening increases IMP1 protein expression and that this in turn enhances the metastatic burden to the liver, whereas expression of the long isoform (full length 3′ UTR) does not. Increased tumor burden results from elevated tumor surface area driven by cell proliferation and cell survival mechanisms. These processes are independent of classical apoptosis pathways. Moreover, we demonstrate the shifts toward the short isoform are associated with metastasis in patient populations where IMP1-long expression predominates. Overall, our work demonstrates that different IMP1 expression levels result in different functional outcomes in CRC metastasis and that targeting IMP1 may reduce tumor progression in some patients.

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Alternative Polyadenylation Patterns for Novel Gene Discovery and Classification in Cancer

Cited by 15 publications

References 31 publications

NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation

NUDT21 inhibits bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation

Alternative polyadenylation of single cells delineates cell types and serves as a prognostic marker in early stage breast cancer

IMP1 3′ UTR shortening enhances metastatic burden in colorectal cancer

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