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The p53-induced RNA-binding protein ZMAT3 is a splicing regulator that inhibits the splicing of oncogenic CD44 variants in colorectal carcinoma.

ABSTRACT: p53 is an intensely studied tumor-suppressive transcription factor. Recent studies suggest that the RNA-binding protein (RBP) ZMAT3 is important in mediating the tumor-suppressive effects of p53. Here, we globally identify ZMAT3-regulated RNAs and their binding sites at nucleotide resolution in intact colorectal cancer (CRC) cells. ZMAT3 binds to thousands of mRNA precursors, mainly at intronic uridine-rich sequences and affects their splicing. The strongest alternatively spliced ZMAT3 target was CD44, a cell adhesion gene and stem cell marker that controls tumorigenesis. Silencing ZMAT3 increased inclusion of CD44 variant exons, resulting in significant up-regulation of oncogenic CD44 isoforms (CD44v) and increased CRC cell growth that was rescued by concurrent knockdown of CD44v Silencing p53 phenocopied the loss of ZMAT3 with respect to CD44 alternative splicing, suggesting that ZMAT3-mediated regulation of CD44 splicing is vital for p53 function. Collectively, our findings uncover a p53-ZMAT3-CD44 axis in growth suppression in CRC cells.

SUBMITTER: Muys BR

PROVIDER: S-EPMC7778265 | biostudies-literature |

REPOSITORIES: biostudies-literature

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p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-12-18 | GSE150718 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_ZMAT3]

Project description:Purpose: p53 is a well-studied protein in which the activation of its main targets is not enough to explain its tumor suppressor effect. Aiming to search for direct p53 targets that mediate less studied processes within p53 pathway, like post-transcriptional regulation, we selected ZMAT3 as the RNA-binding protein most upregulated by p53 activation. Methods: We investigated ZMAT3 targets by using PAR-CLIP and RNA-seq in colorectal cancer cell line HCT116. Results.txt: We found that ZMAT3 binds to ~5000 genes mainly in their introns. It also causes alternative splicing and CD44 was its mostly altered target. ZMAT3 knock-down increased CD44v2-v10 and CD44v3-v10, but decreased CD44s expression. Increased survival and clonogenicity was observed upon knock-down of ZMAT3, which was rescued upon concurrent knock-down of CD44v Conclusions: We propose that ZMAT3 regulates splicing of CD44 following activation by p53, which upregulates CD44s at the expense of CD44v isoforms and leads to a decrease tumorigenicity.

2020-12-18 | GSE150717 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_UPF1]

2020-12-18 | GSE150716 | GEO

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [PAR-CLIP_ZMAT3]

Project description:Purpose: p53 is a well-studied protein in which the activation of its main targets is not enough to explain its tumor suppressor effect. Aiming to search for direct p53 targets that mediate less studied processes within p53 pathway, like post-transcriptional regulation, we selected ZMAT3 as the RNA-binding protein most upregulated by p53 activation. Methods: We investigated ZMAT3 targets by using PAR-CLIP and RNA-seq in colorectal cancer cell line HCT116. Results: We found that ZMAT3 binds to ~5000 genes mainly in their introns. It also causes alternative splicing and CD44 was its mostly altered target. ZMAT3 knock-down increased CD44v2-v10 and CD44v3-v10, but decreased CD44s expression. Increased survival and clonogenicity was observed upon knock-down of ZMAT3, which was rescued upon concurrent knock-down of CD44v Conclusions: We propose that ZMAT3 regulates splicing of CD44 following activation by p53, which upregulates CD44s at the expense of CD44v isoforms and leads to a decrease tumorigenicity.

2020-12-18 | GSE150715 | GEO

Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program.

Project description:Although TP53 is the most commonly mutated gene in human cancers, the p53-dependent transcriptional programs mediating tumor suppression remain incompletely understood. Here, to uncover critical components downstream of p53 in tumor suppression, we perform unbiased RNAi and CRISPR-Cas9-based genetic screens in vivo. These screens converge upon the p53-inducible gene Zmat3, encoding an RNA-binding protein, and we demonstrate that ZMAT3 is an important tumor suppressor downstream of p53 in mouse KrasG12D-driven lung and liver cancers and human carcinomas. Integrative analysis of the ZMAT3 RNA-binding landscape and transcriptomic profiling reveals that ZMAT3 directly modulates exon inclusion in transcripts encoding proteins of diverse functions, including the p53 inhibitors MDM4 and MDM2, splicing regulators, and components of varied cellular processes. Interestingly, these exons are enriched in NMD signals, and, accordingly, ZMAT3 broadly affects target transcript stability. Collectively, these studies reveal ZMAT3 as a novel RNA-splicing and homeostasis regulator and a key component of p53-mediated tumor suppression.

| S-EPMC7654708 | biostudies-literature

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC

Project description:p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC

| PRJNA633366 | ENA

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_ZMAT3]

Project description:p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_ZMAT3]

| PRJNA633369 | ENA

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [PAR-CLIP_ZMAT3]

Project description:p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [PAR-CLIP_ZMAT3]

| PRJNA633362 | ENA

p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_UPF1]

Project description:p53-induced RNA-binding protein ZMAT3 is splicing regulator that inhibits the splicing of oncogenic CD44 variants in CRC [RNA-seq_UPF1]

| PRJNA633368 | ENA

WNT5A inhibits metastasis and alters splicing of Cd44 in breast cancer cells.

Project description:Wnt5a is a non-canonical signaling Wnt. Low expression of WNT5A is correlated with poor prognosis in breast cancer patients. The highly invasive breast cancer cell lines, MDA-MB-231 and 4T1, express very low levels of WNT5A. To determine if enhanced expression of WNT5A would affect metastatic behavior, we generated WNT5A expressing cells from the 4T1 and MDA-MB-231 parental cell lines. WNT5A expressing cells demonstrated cobblestone morphology and reduced in vitro migration relative to controls. Cell growth was not altered. Metastasis to the lung via tail vein injection was reduced in the 4T1-WNT5A expressing cells relative to 4T1-vector controls. To determine the mechanism of WNT5A action on metastasis, we performed microarray and whole-transcriptome sequence analysis (RNA-seq) to compare gene expression in 4T1-WNT5A and 4T1-vector cells. Analysis indicated highly significant alterations in expression of genes associated with cellular movement. Down-regulation of a subset of these genes, Mmp13, Nos2, Il1a, Cxcl2, and Lamb3, in WNT5A expressing cells was verified by semi-quantitative RT-PCR. Significant differences in transcript splicing were also detected in cell movement associated genes including Cd44. Cd44 is an adhesion molecule with a complex genome structure. Variable exon usage is associated with metastatic phenotype. Alternative spicing of Cd44 in WNT5A expressing cells was confirmed using RT-PCR. We conclude that WNT5A inhibits metastasis through down-regulation of multiple cell movement pathways by regulating transcript levels and splicing of key genes like Cd44.

| S-EPMC3590134 | biostudies-literature

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