Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 02 2023
10 02 2023
Historique:
received:
26
04
2022
accepted:
30
01
2023
pubmed:
11
2
2023
medline:
15
2
2023
entrez:
10
2
2023
Statut:
epublish
Résumé
MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.
Identifiants
pubmed: 36765089
doi: 10.1038/s41467-023-36400-8
pii: 10.1038/s41467-023-36400-8
pmc: PMC9918503
doi:
Substances chimiques
Phosphoric Monoester Hydrolases
EC 3.1.3.2
Proto-Oncogene Proteins c-myc
0
CTDNEP1 protein, human
EC 3.1.3.16
Phosphoprotein Phosphatases
EC 3.1.3.16
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
762Subventions
Organisme : NCI NIH HHS
ID : P01 CA096832
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA117846
Pays : United States
Informations de copyright
© 2023. The Author(s).
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