Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG.
Aging
/ genetics
Astrocytoma
/ genetics
Brain Stem Neoplasms
/ drug therapy
Cell Differentiation
/ genetics
Cell Line, Tumor
Cell Proliferation
/ drug effects
Child
Child, Preschool
Chromatin
/ genetics
Diffuse Intrinsic Pontine Glioma
/ drug therapy
Epigenomics
Female
Glioma
/ drug therapy
Histones
/ metabolism
Humans
Lysine
/ metabolism
Male
Mutation
Neoplasm Recurrence, Local
/ drug therapy
Polycomb Repressive Complex 1
/ antagonists & inhibitors
BH3 mimetics
BMI1
DIPG
H3K27M mutant
H3WT
PTC 028
RNAi screen
SASP
senescence
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
20 10 2020
20 10 2020
Historique:
received:
30
12
2019
revised:
05
07
2020
accepted:
25
09
2020
entrez:
21
10
2020
pubmed:
22
10
2020
medline:
21
10
2021
Statut:
ppublish
Résumé
Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
Identifiants
pubmed: 33086074
pii: S2211-1247(20)31275-4
doi: 10.1016/j.celrep.2020.108286
pmc: PMC7574900
pii:
doi:
Substances chimiques
BMI1 protein, human
0
Chromatin
0
Histones
0
Polycomb Repressive Complex 1
EC 2.3.2.27
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
108286Subventions
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NIH HHS
ID : S10 OD023485
Pays : United States
Organisme : NIH HHS
ID : S10 OD027023
Pays : United States
Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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