In:
Genes & Development, Cold Spring Harbor Laboratory, Vol. 35, No. 1-2 ( 2021-01-01), p. 102-116
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.
Type of Medium:
Online Resource
ISSN:
0890-9369
,
1549-5477
DOI:
10.1101/gad.342634.120
Language:
English
Publisher:
Cold Spring Harbor Laboratory
Publication Date:
2021
detail.hit.zdb_id:
1467414-2
SSG:
12
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