Targeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells.
Animals
Cell Differentiation
/ drug effects
Cell Proliferation
/ drug effects
Cell Self Renewal
/ drug effects
Colorectal Neoplasms
/ metabolism
Enhancer of Zeste Homolog 2 Protein
/ metabolism
Female
Fluorouracil
/ pharmacology
Hedgehog Proteins
/ metabolism
Humans
Male
Mice, Inbred NOD
Mice, SCID
Neoplastic Stem Cells
/ drug effects
Pyridones
/ pharmacology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 03 2019
29 03 2019
Historique:
received:
03
09
2018
accepted:
27
02
2019
entrez:
31
3
2019
pubmed:
31
3
2019
medline:
6
5
2019
Statut:
epublish
Résumé
In embryonic stem cells, promoters of key lineage-specific differentiation genes are found in a bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3. Whether cancer-initiating cells (C-ICs) have similar epigenetic mechanisms that prevent lineage commitment is unknown. Here we show that colorectal C-ICs (CC-ICs) are maintained in a stem-like state through a bivalent epigenetic mechanism. Disruption of the bivalent state through inhibition of the H3K27 methyltransferase EZH2, resulted in decreased self-renewal of patient-derived C-ICs. Epigenomic analyses revealed that the promoter of Indian Hedgehog (IHH), a canonical driver of normal colonocyte differentiation, exists in a bivalent chromatin state. Inhibition of EZH2 resulted in de-repression of IHH, decreased self-renewal, and increased sensitivity to chemotherapy in vivo. Our results reveal an epigenetic block to differentiation in CC-ICs and demonstrate the potential for epigenetic differentiation therapy of a solid tumour through EZH2 inhibition.
Identifiants
pubmed: 30926792
doi: 10.1038/s41467-019-09309-4
pii: 10.1038/s41467-019-09309-4
pmc: PMC6441108
doi:
Substances chimiques
Hedgehog Proteins
0
IHH protein, human
0
Pyridones
0
UNC1999
0
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Fluorouracil
U3P01618RT
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
1436Subventions
Organisme : NCI NIH HHS
ID : R01 CA218600
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM122749
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : R01 HD088626
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230854
Pays : United States
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