Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation.
Acetylation
Animals
Apoptosis
/ genetics
Cell Line, Tumor
Cell Self Renewal
/ genetics
Chromatin
/ metabolism
DNA Methylation
DNA Repair
/ genetics
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Glioblastoma
/ genetics
HEK293 Cells
Histones
Humans
Jumonji Domain-Containing Histone Demethylases
/ genetics
Lysine
/ metabolism
Mice
Neoplastic Stem Cells
/ metabolism
Promoter Regions, Genetic
/ genetics
RNA, Small Interfering
/ metabolism
Xenograft Model Antitumor Assays
DNA repair
cancer stem cells
heterochromatin
histone acetylation
histone methylation
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 03 2020
01 03 2020
Historique:
received:
07
03
2019
revised:
11
07
2019
accepted:
30
07
2019
pubmed:
29
8
2019
medline:
15
2
2020
entrez:
29
8
2019
Statut:
ppublish
Résumé
Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DNA damage response genes. Upon knockdown of histone demethylases, KDM4C and KDM7A both differentiation and DNA damage were induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.
Substances chimiques
Chromatin
0
Histones
0
RNA, Small Interfering
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1281-1292Informations de copyright
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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