The Proto-Oncogene TWIST1 Is Regulated by MicroRNAs

Nairismagi, Maarja-Liisa; Füchtbauer, Annette; Labouriau, Rodrigo; Bramsen, Jesper B.; Füchtbauer, Ernst‐Martin

doi:10.1371/journal.pone.0066070

Cited by 26 publications

(20 citation statements)

References 61 publications

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“…Control of BCL2 expression via miR-24-2 (strongly upregulated in both proximal and distal tumors), has been previously reported in human embryonic kidney and breast cancer cell lines [47]. Interestingly, several uniquely regulated miRs correlate significantly with (hypermethylated) TWIST1, a primal transcription factor uniquely upregulated within proximal tumors [48], whose activation has been implicated in reverting cells to a non-lineage specific proliferative state. Only two miRs however, are uniquely regulated within distal tumors-miR-3607 and miR-29a (Fig.…”

Section: Rscc Exhibits Pronounced Post-transcriptional Regulationmentioning

confidence: 65%

Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

et al. 2020

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Background: Given the differences in embryonic origin, vascular and nervous supplies, microbiotic burden, and main physiological functions of left and right colons, tumor location is increasingly suggested to dictate tumor behavior affecting pathology, progression and prognosis. Right-sided colon cancers arise in the cecum, ascending colon, hepatic flexure and/or transverse colon, while left-sided colon cancers arise in the splenic flexure, descending, and/or sigmoid colon. In contrast to prior reports, we attempt to delineate programs of tumorigenesis independently for each side. Methods: Four hundred and eleven samples were extracted from The Cancer Genome Atlas-COAD cohort, based on a conservative sample inclusion criterion. Each side was independently analyzed with respect to their respective normal tissue, at the level of transcription, post-transcription, miRNA control and methylation in both a stage specific and stage-agnostic manner. Results: Our results indicate a suppression of enzymes involved in various stages of carcinogen breakdown including CYP2C8, CYP4F12, GSTA1, and UGT1A within right colon tumors. This implies its reduced capacity to detoxify carcinogens, contributing to a genotoxic tumor environment, and subsequently a more aggressive phenotype. Additionally, we highlight a crucial nexus between calcium homeostasis (sensing, mobilization and absorption) and immune/GPCR signaling within left-sided tumors, possibly contributing to its reduced proliferative and metastatic potential. Interestingly, two genes SLC6A4 and HOXB13 show opposing regulatory trends within right and left tumors. Post-transcriptional regulation mediated by both RNA-binding proteins (e.g. NKRF (in left) and MSI2 (in right)) and miRNAs (e.g. miR-29a (in left); miR-155, miR181-d, miR-576 and miR23a (in right)) appear to exhibit side-specificity in control of their target transcripts and is pronounced in right colon tumors. Additionally, methylation results depict location-specific differences, with increased hypomethylation in open seas within left tumors, and increased hypermethylation of CpG islands within right tumors. Conclusions: Differences in molecular mechanisms captured here highlight distinctions in tumorigenesis and progression between left and right colon tumors, which will serve as the basis for future studies, influencing the efficacies of existing and future diagnostic, prognostic and therapeutic interventions.

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Section: Rscc Exhibits Pronounced Post-transcriptional Regulationmentioning

confidence: 65%

Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

et al. 2020

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“…It was also found that miR-151-3p represses the full-length isoform of human neurotrophin-3 receptor gene NTRK3 in neuroblastoma cells [37]. It was recently demonstrated that miR-151-5p and a combination of other miRNAs (miR-145a-5p or miR-337-3p) are able to significantly repress TWIST1translation and result in decreased migratory potential of murine embryonic fibroblast cells [19]. In the role of miR-151-3p in muscle fiber type determination, miR-151-3p was shown to directly target ATP2a2, a gene that encodes for a slow skeletal and cardiac muscle specific Ca 2+ ATPase known as SERCA2, thus downregulating slow muscle gene expression [38].…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, miR-151-5p expression levels were not different among tumors of varying grades, but the level was significantly lower in the lymph-node metastases than in their corresponding tumors of breast cancer patients [18]. It was recently demonstrated that miR-151-5p combined with other miRNAs (miR-145a-5p or miR-337-3p) are able to significantly repress TWIST1 translation and result in the decreased migratory potential of murine embryonic fibroblast cells [19]. However, the role of miR-151 in breast cancer progression and its direct targets in the regulation of breast cancer metastasis are still undefined.…”

Section: Introductionmentioning

confidence: 99%

miR-151-3p Targets TWIST1 to Repress Migration of Human Breast Cancer Cells

Yeh¹,

Huang²,

Yeh³

et al. 2016

PLoS ONE

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TWIST1 is a highly conserved basic helix-loop-helix transcription factor that contributes to cancer metastasis by promoting an epithelial-mesenchymal transition and repressing E-cadherin gene expression in breast cancer. In this study, we explored the potential role of miR-151 in TWIST1 expression and cancer properties in human breast cancer cells. We found that the human TWIST1 3’UTR contains a potential binging site for miR-151-3p at the putative target sequence 5’-CAGUCUAG-3’. Using a TWIST1-3’UTR luciferase reporter assay, we demonstrated that the target sequence within the TWIST1 3’UTR is required for miR-151-3p regulation of TWIST1 expression. Moreover, we found that ectopic expression of miR-151-3p by infection with adenoviruses expressing miR-151 significantly decreased TWIST1 expression, migration and invasion, but did not affect cell growth and tumorsphere formation of human breast cancer cells. In addition, overexpression of the protein coding region without the 3’UTR of TWIST1 reversed the repression of cell migration by miR-151-3p. Furthermore, knockdown of miR-151-3p increased TWIST1 expression, reduced E-cadherin expression, and enhanced cell migration. In conclusion, these results suggest that miR-151-3p directly regulates TWIST1 expression by targeting the TWIST1 3’UTR and thus repressing the migration and invasion of human breast cancer cells by enhancing E-cadherin expression. Our findings add to accumulating evidence that microRNAs are involved in breast cancer progression by modulating TWIST1 expression.

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“…Interestingly, differences in the mRNA levels of these DNA trans-factors were not observed in these NGS data. Because CPEB2 has been implicated as a translational repressor of TWIST1 and HIF1␣ (10,11), our findings coupled to these published reports formed the premise that CPEB2A is the suppressing form of CPEB2 on TWIST1 protein expression as reported by others (9,10), whereas CPEB2B has the previously unexplored function of activating the expression of these DNA trans-factors in response to cellular stress or the acquisition of AnR. In line with this premise, we observed that both HIF1␣ and TWIST1 were up-regulated in AnR MDA-MB-231 cells, which correlated with a decrease in the CPEB2A/ CPEB2B ratio ( Fig.…”

Section: Cpeb2 Rna Splicing Regulates Emt and Hypoxic Responsesmentioning

confidence: 99%

Splice variants of cytosolic polyadenylation element–binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis

DeLigio¹,

Lin²,

Chalfant

et al. 2017

Journal of Biological Chemistry

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The translational regulator cytosolic polyadenylation element-binding protein 2 (CPEB2) has two isoforms, CPEB2A and CPEB2B, derived by alternative splicing of RNA into a mature form that either includes or excludes exon 4. Previously, we reported that this splicing event is highly dysregulated in aggressive forms of breast cancers, which overexpress CPEB2B. The loss of CPEB2A with a concomitant increase in CPEB2B was also required for breast cancer cells to resist cell death because of detachment (anoikis resistance) and metastasize To examine the mechanism by which CPEB2 isoforms mediate opposing effects on cancer-related phenotypes, we used next generation sequencing of triple negative breast cancer cells in which the isoforms were specifically down-regulated. Down-regulation of the CPEB2B isoform inhibited pathways driving the epithelial-to-mesenchymal transition and hypoxic response, whereas down-regulation of the CPEB2A isoform did not have this effect. Examining key nodes of these pathways showed that CPEB2B induced the expression of regulatory DNA-factors ( HIF1α and TWIST1). Specifically, CPEB2B functioned as a translational activator of TWIST1 and HIF1α. Functional studies showed that specific down-regulation of either HIF1α or TWIST1 inhibited the ability of CPEB2B to induce the acquisition of anoikis resistance and drive metastasis. Overall, this study demonstrates that CPEB2 alternative splicing is a major regulator of key cellular pathways linked to anoikis resistance and metastasis.

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The Proto-Oncogene TWIST1 Is Regulated by MicroRNAs

Cited by 26 publications

References 61 publications

Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

miR-151-3p Targets TWIST1 to Repress Migration of Human Breast Cancer Cells

Splice variants of cytosolic polyadenylation element–binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis

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