17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma.
Cancer
Molecular Biology
Omics
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
22 Jan 2021
22 Jan 2021
Historique:
received:
09
04
2020
revised:
09
06
2020
accepted:
23
12
2020
entrez:
25
1
2021
pubmed:
26
1
2021
medline:
26
1
2021
Statut:
epublish
Résumé
Histone lysine demethylases (KDMs) play critical roles in oncogenesis and therefore may be effective targets for anticancer therapy. Using a time-resolved fluorescence resonance energy transfer demethylation screen assay, in combination with multiple orthogonal validation approaches, we identified geldanamycin and its analog 17-DMAG as KDM inhibitors. In addition, we found that these Hsp90 inhibitors increase degradation of the alveolar rhabdomyosarcoma (aRMS) driver oncoprotein PAX3-FOXO1 and induce the repressive epigenetic mark H3K9me3 and H3K36me3 at genomic loci of PAX3-FOXO1 targets. We found that as monotherapy 17-DMAG significantly inhibits expression of PAX3-FOXO1 target genes and multiple oncogenic pathways, induces a muscle differentiation signature, delays tumor growth and extends survival in aRMS xenograft mouse models. The combination of 17-DMAG with conventional chemotherapy significantly enhances therapeutic efficacy, indicating that targeting KDM in combination with chemotherapy may serve as a therapeutic approach to PAX3-FOXO1-positive aRMS.
Identifiants
pubmed: 33490904
doi: 10.1016/j.isci.2020.101996
pii: S2589-0042(20)31193-7
pmc: PMC7811140
doi:
Types de publication
Journal Article
Langues
eng
Pagination
101996Subventions
Organisme : NCI NIH HHS
ID : R01 CA229739
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA212802
Pays : United States
Informations de copyright
© 2020 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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