NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1.
Alterative polyadenylation
LAMC1
NUDT21
PolyA-miner
Journal
Journal of neuro-oncology
ISSN: 1573-7373
Titre abrégé: J Neurooncol
Pays: United States
ID NLM: 8309335
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
04
05
2023
accepted:
09
06
2023
medline:
2
8
2023
pubmed:
30
6
2023
entrez:
30
6
2023
Statut:
ppublish
Résumé
Gliomas and their surrounding microenvironment constantly interact to promote tumorigenicity, yet the underlying posttranscriptional regulatory mechanisms that govern this interplay are poorly understood. Utilizing our established PAC-seq approach and PolyAMiner bioinformatic analysis pipeline, we deciphered the NUDT21-mediated differential APA dynamics in glioma cells. We identified LAMC1 as a critical NUDT21 alternative polyadenylation (APA) target, common in several core glioma-driving signaling pathways. qRT-PCR analysis confirmed that NUDT21-knockdown in glioma cells results in the preferred usage of the proximal polyA signal (PAS) of LAMC1. Functional studies revealed that NUDT21-knockdown-induced 3'UTR shortening of LAMC1 is sufficient to cause translational gain, as LAMC1 protein is upregulated in these cells compared to their respective controls. We demonstrate that 3'UTR shortening of LAMC1 after NUDT21 knockdown removes binding sites for miR-124/506, thereby relieving potent miRNA-based repression of LAMC1 expression. Remarkably, we report that the knockdown of NUDT21 significantly promoted glioma cell migration and that co-depletion of LAMC1 with NUDT21 abolished this effect. Lastly, we observed that LAMC1 3'UTR shortening predicts poor prognosis of low-grade glioma patients from The Cancer Genome Atlas. This study identifies NUDT21 as a core alternative polyadenylation factor that regulates the tumor microenvironment through differential APA and loss of miR-124/506 inhibition of LAMC1. Knockdown of NUDT21 in GBM cells mediates 3'UTR shortening of LAMC1, contributing to an increase in LAMC1, increased glioma cell migration/invasion, and a poor prognosis.
Identifiants
pubmed: 37389756
doi: 10.1007/s11060-023-04370-y
pii: 10.1007/s11060-023-04370-y
doi:
Substances chimiques
3' Untranslated Regions
0
MicroRNAs
0
Nudt21 protein, human
0
laminin gamma 1
0
Cleavage And Polyadenylation Specificity Factor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
623-634Subventions
Organisme : NIH HHS
ID : R03 CA223893-01
Pays : United States
Organisme : NIH HHS
ID : R01CA193466-01
Pays : United States
Organisme : NIH HHS
ID : R03 CA223893-01
Pays : United States
Organisme : NIH HHS
ID : R01CA193466-01
Pays : United States
Organisme : NIH HHS
ID : R01CA193466-01
Pays : United States
Organisme : NIH HHS
ID : R03 CA223893-01
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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