The p53-induced RNA-binding protein ZMAT3 is a splicing regulator that inhibits the splicing of oncogenic CD44 variants in colorectal carcinoma
| Autor: | Ioannis Grammatikakis, Ashish Lal, Lorinc Pongor, Xiantao Wang, Duncan Claypool, Bruna Rodrigues Muys, Mirit I. Aladjem, Markus Hafner, Minxue Liu, Xiaoling Li, Kannanganattu V. Prasanth, Dimitrios G. Anastasakis |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Carcinogenesis
RNA Splicing RNA-binding protein 03 medical and health sciences Exon 0302 clinical medicine RNA Precursors Genetics Humans Gene silencing Gene Silencing Transcription factor 030304 developmental biology 0303 health sciences Gene knockdown biology Alternative splicing CD44 RNA-Binding Proteins HCT116 Cells Cell biology Alternative Splicing HEK293 Cells Hyaluronan Receptors Gene Knockdown Techniques 030220 oncology & carcinogenesis RNA splicing biology.protein Tumor Suppressor Protein p53 Colorectal Neoplasms Research Paper Protein Binding Developmental Biology |
| Zdroj: | Genes Dev |
| ISSN: | 1549-5477 0890-9369 |
| DOI: | 10.1101/gad.342634.120 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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