Alternative polyadenylation factors link cell cycle to migration

Mitra, Mithun; Johnson, Elizabeth L.; Swamy, Vinay; Nersesian, Lois E; Corney, David C.; Robinson, David G.; Taylor, Daniel; Ambrus, Aaron M.; Jelínek, David; Wang, Wei; Batista, Sandra; Coller, Hilary A.

doi:10.1186/s13059-018-1551-9

Cited by 27 publications

(34 citation statements)

References 113 publications

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“…An asymmetric pattern of IR change has also been associated with changes in cellular state. For example, differentiated and quiescent cells have higher IR levels compared to proliferating cells 48,[75][76][77] . In yeast, intron retention in the Gcr transcription factor has been associated with changes in nutrient status and the isoforms with and without the intron were both required for expression of target genes involved in glycolysis 78 .…”

Section: Discussionmentioning

confidence: 99%

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of <8%. Unsupervised clustering of 76 PDAC patients based on intron retention (IR) events resulted in two clusters of tumors (IR-1 and IR-2). While gene expression-based clusters are not predictive of patient outcome in this cohort, the clusters we developed based on intron retention were associated with differences in progression-free interval. IR levels are lower and clinical outcome is worse in IR-1 compared with IR-2. Oncogenes were significantly enriched in the set of 262 differentially retained introns between the two IR clusters. Higher IR levels in IR-2 correlate with higher gene expression, consistent with detention of intron-containing transcripts in the nucleus in IR-2. Out of 258 genes encoding RNA-binding proteins (RBP) that were differentially expressed between IR-1 and IR-2, the motifs for seven RBPs were significantly enriched in the 262-intron set, and the expression of 25 RBPs were highly correlated with retention levels of 139 introns. Network analysis suggested that retention of introns in IR-2 could result from disruption of an RBP protein−protein interaction network previously linked to efficient intron removal. Finally, IR-based clusters developed for the majority of the 20 cancer types surveyed had two clusters with asymmetrical distributions of IR events like PDAC, with one cluster containing mostly intron loss events. Taken together, our findings suggest IR may be an important biomarker for subclassifying tumors.

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Section: Discussionmentioning

confidence: 99%

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

et al. 2020

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“…APA has recently been identified as a candidate driver of gene expression dysregulation. APA factors frequently show aberrant expression in cancer, modulate the expression of known oncogenes and tumor suppressors, and knockdown studies have highlighted their relevance to the cancer phenotype 31–34,102,103 . Whole-genome CRISPR and shRNA screens have also revealed the requirement for several APA factors in pancreatic cancer cell growth (www.depmap.org).…”

Section: Discussionmentioning

confidence: 99%

“…4). CSTF2 has previously been implicated as a promoter of lung and bladder cancer, through the regulation of ERBB2 and RAC1 3’-UTRs, respectively 33,34 . We find frequent 3’-UTR alterations in several notable PDA-relevant genes whose mechanisms of regulation were previously unknown, including PAF1 , ALDOA and FLNA .…”

Section: Discussionmentioning

confidence: 99%

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Venkat

Tisdale

Schwarz

et al. 2019

Preprint

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Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3’-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDAs). We report widespread, recurrent and functionally relevant 3’-UTR alterations associated with gene expression changes of known and newly identified PDA growth-promoting genes and experimentally validate the effects of these APA events on expression. We find enrichment for APA events in genes associated with known PDA pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3’-UTR forms of metabolic genes. Survival analyses reveal a subset of 3’-UTR alterations that independently characterize a poor prognostic cohort among PDA patients. Finally, we identify and validate the casein kinase CK1α as an APA-regulated therapeutic target in PDA. Knockdown or pharmacological inhibition of CK1α attenuates PDA cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of pro-tumorigenic gene expression in PDA via the loss of miRNA regulation.

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“…CFIm25 is known to be crucial in controlling invasion and metastasis of HCC 32 . It is also confirmed that www.nature.com/scientificreports/ activation of APA sites can affect the migratory capacity of cancer cells 33 as well as fibroblasts 34 . According to the results of wound healing assay, regulation of CFIm25 expression by miR-23 and 374 directly controls breast cancer cells' migration and invasion.…”

Section: Discussionmentioning

confidence: 62%

Involved microRNAs in alternative polyadenylation intervene in breast cancer via regulation of cleavage factor “CFIm25”

Tamaddon

Shokri

Rad

et al. 2020

Sci Rep

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Cleavage factor "CFIm25", as a key repressor at proximal poly (A) site, negatively correlates to cell proliferation and tumorigenicity in various cancers. Hence, understanding CFIm25 mechanism of action in breast cancer would be a great benefit. To this aim four steps were designed. First, potential miRNAs that target 3′-UtR of CFIm25 mRnA, retrieved from targetscan web server. Second, screened miRNAs were profiled in 100 breast cancer and 100 normal adjacent samples. Third, miRNAs that their expression was inversely correlated to the CFIm25, overexpressed in MDA-MB-231 cell line, and their effect on proliferation and migration monitored via MTT and wound healing assays, respectively. fourth, interaction of miRNAs of interest with 3′-UtR of CFIm25 confirmed via luciferase assay and western blot. our results indicate that CFIm25 considerably down-regulates in human breast cancer tissue. qRT-PCR assay, luciferase test, and western blotting confirm that CFIm25 itself could be directly regulated by oncomiRs such as miR-23,-24,-27,-135,-182 and-374. Besides, according to Mtt and wound healing assays of cell lines, CFIm25 knockdown intensifies cell growth, proliferation and migration. Our results also confirm indirect impact of CFIm25 on regulation of mRNA's 3′-UtR length, which then control corresponding miRNAs' action. miRNAs directly control CFIm25 expression level, which then tunes expression of the oncogenes and tumor proliferation. Therefore, regulation of CFIm25 expression level via miRNAs is expected to improve treatment responses in breast cancer. Abbreviations CPSF Cleavage and polyadenylation specificity factor CstF Cleavage stimulation factor PAS Polyadenylation site 3′-UTR 3′-Untranslated region UTR-APA Untranslated region-alternative polyadenylation miRNA/miR MicroRNA CFIm25 Cleavage factor Im 25 RF Random forest classifiers shRNA Short hairpin RNA HCC Hepatocellular carcinoma Living organisms apply complicated mechanisms of gene regulation to generate different cell types, which result in various behaviors from a single genome 1,2. Dynamic and highly polymorphic nature of mRNA polyadenylation, as a functional aspect of gene regulation, is one of the most recent discoveries in this field 3,4. Cleavage and polyadenylation of nascent mRNA accomplishes via application of two large multimeric complexes, which named as cleavage-polyadenylation specificity factor (CPSF) and cleavage stimulation factor (CstF), respectively. The

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Alternative polyadenylation factors link cell cycle to migration

Cited by 27 publications

References 113 publications

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma

Involved microRNAs in alternative polyadenylation intervene in breast cancer via regulation of cleavage factor “CFIm25”

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