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

Bruna R. Muys, Dimitrios G. Anastasakis, Duncan Claypool, Lörinc Pongor, Xiao Ling Li, Ioannis Grammatikakis, Minxue Liu, Xiantao Wang, Kannanganattu V. Prasanth, Mirit I. Aladjem, Ashish Lal, Markus Hafner

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)102-116
Number of pages15
JournalGenes and Development
Volume35
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • CD44
  • Colorectal carcinoma
  • P53
  • PAR-CLIP]
  • RBP
  • RNA-binding protein
  • Splicing
  • ZMAT3

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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