NeuroD1 Dictates Tumor Cell Differentiation in Medulloblastoma.
Animals
Basic Helix-Loop-Helix Transcription Factors
/ metabolism
Carcinogenesis
/ pathology
Cell Differentiation
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms
/ pathology
Enhancer of Zeste Homolog 2 Protein
/ metabolism
Hedgehog Proteins
/ metabolism
Histones
/ metabolism
Humans
Lysine
/ metabolism
Medulloblastoma
/ pathology
Methylation
Mice
Nerve Tissue Proteins
/ metabolism
Neurons
/ metabolism
Patched-1 Receptor
/ metabolism
Signal Transduction
Single-Cell Analysis
EZH2 inhibitors
H3k27me3
NeuroD1
Tag1
differentiation therapy
epigenetic compound screening
granule neuron precursors
hedgehog signaling
medulloblastoma
tumor cell differentiation
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
23 06 2020
23 06 2020
Historique:
received:
06
09
2019
revised:
01
04
2020
accepted:
27
05
2020
entrez:
25
6
2020
pubmed:
25
6
2020
medline:
29
4
2021
Statut:
ppublish
Résumé
Tumor cells are characterized by unlimited proliferation and perturbed differentiation. Using single-cell RNA sequencing, we demonstrate that tumor cells in medulloblastoma (MB) retain their capacity to differentiate in a similar way as their normal originating cells, cerebellar granule neuron precursors. Once they differentiate, MB cells permanently lose their proliferative capacity and tumorigenic potential. Differentiated MB cells highly express NeuroD1, a helix-loop-helix transcription factor, and forced expression of NeuroD1 promotes the differentiation of MB cells. The expression of NeuroD1 in bulk MB cells is repressed by trimethylation of histone 3 lysine-27 (H3K27me3). Inhibition of the histone lysine methyltransferase EZH2 prevents H3K27 trimethylation, resulting in increased NeuroD1 expression and enhanced differentiation in MB cells, which consequently reduces tumor growth. These studies reveal the mechanisms underlying MB cell differentiation and provide rationales to treat MB (potentially other malignancies) by stimulating tumor cell differentiation.
Identifiants
pubmed: 32579914
pii: S2211-1247(20)30762-2
doi: 10.1016/j.celrep.2020.107782
pmc: PMC7357167
mid: NIHMS1607415
pii:
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Hedgehog Proteins
0
Histones
0
Nerve Tissue Proteins
0
Patched-1 Receptor
0
Ptch1 protein, mouse
0
Neurogenic differentiation factor 1
169238-82-8
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Ezh2 protein, mouse
EC 2.1.1.43
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107782Subventions
Organisme : NCI NIH HHS
ID : R01 CA178380
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.