Dual inhibition of enhancer of zeste homolog 1/2 overactivates WNT signaling to deplete cancer stem cells in multiple myeloma.
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Enhancer of Zeste Homolog 2 Protein
/ antagonists & inhibitors
Enzyme Inhibitors
/ pharmacology
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Multiple Myeloma
/ genetics
Neoplastic Stem Cells
/ drug effects
Polycomb Repressive Complex 2
/ antagonists & inhibitors
Side-Population Cells
/ drug effects
Wnt Signaling Pathway
/ drug effects
Xenograft Model Antitumor Assays
EZH1/2 dual inhibitor
PRC2
WNT signaling
multiple myeloma
myeloma stem cell
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Jan 2019
Jan 2019
Historique:
received:
09
08
2018
revised:
09
10
2018
accepted:
11
10
2018
pubmed:
22
10
2018
medline:
15
1
2019
entrez:
22
10
2018
Statut:
ppublish
Résumé
Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells show cancer stem cell-like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient-derived xenograft model. Moreover, long-term continuous dosing of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR-S1, leading to significant advances in the treatment of MM.
Identifiants
pubmed: 30343511
doi: 10.1111/cas.13840
pmc: PMC6317945
doi:
Substances chimiques
Enzyme Inhibitors
0
EZH1 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Polycomb Repressive Complex 2
EC 2.1.1.43
Banques de données
GENBANK
['WO2015', 'UNC1999']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
194-208Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP18K16101
Organisme : Japan Agency for Medical Research and Development
Organisme : National Cancer Center Research and Development Fund
Informations de copyright
© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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