@article{1a944aeb6e46436fb7513f7d170985ba,
title = "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.",
keywords = "CD44, Colorectal carcinoma, P53, PAR-CLIP], RBP, RNA-binding protein, Splicing, ZMAT3",
author = "Muys, {Bruna R.} and Anastasakis, {Dimitrios G.} and Duncan Claypool and L{\"o}rinc Pongor and Li, {Xiao Ling} and Ioannis Grammatikakis and Minxue Liu and Xiantao Wang and Prasanth, {Kannanganattu V.} and Aladjem, {Mirit I.} and Ashish Lal and Markus Hafner",
note = "Funding Information: This work was supported by the Intramural Research Programs of the National Cancer Institute (NCI), the Center for Cancer Research (CCR), and the National Institute for Arthritis and Musculoskeletal and Skin Disease (NIAMS). We thank the NIAMS Genomics Core Facility as well as Gustavo Gutierrez-Cruz and Dr. Stefania Dell{\textquoteright}Orso (NIAMS/National Institutes of Health [NIH]) for sequencing support. We also thank the NCI core sequencing facility for performing part of the RNA-seq. Work in K.V.P.{\textquoteright}s laboratory was supported by grants from NIH (R21AG065748 and R01GM132458), a Cancer Center at Illinois seed grant, the Prairie Dragon Paddlers, and the National Science Foundation (EAGER; MCB1723008). We thank Dr. Glenn Merlino (NCI) for his insightful comments on our manuscript. Funding Information: This work was supported by the Intramural Research Programs of the National Cancer Institute (NCI), the Center for Cancer Research (CCR), and the National Institute for Arthritis and Musculoskeletal and Skin Disease (NIAMS). We thank the NIAMS Genomics Core Facility as well as Gustavo Gutierrez-Cruz and Dr. Stefania Dell{\textquoteright}Orso (NIAMS/National Institutes of Health [NIH]) for sequencing support. We also thank the NCI core sequencing facility for performing part of the RNA-seq. Work in K.V.P.{\textquoteright}s laboratory was supported by grants from NIH (R21AG065748 and R01GM132458), a Cancer Center at Illinois seed grant, the Prairie Dragon Paddlers, and the National Science Foundation (EAGER; MCB1723008). We thank Dr. Glenn Mer-lino (NCI) for his insightful comments on our manuscript. Publisher Copyright: {\textcopyright} 2021 Muys et al.",
year = "2021",
month = jan,
day = "1",
doi = "10.1101/GAD.342634.120",
language = "English (US)",
volume = "35",
pages = "102--116",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "1",
}