文章基本信息

标题：17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma
本地全文：下载
作者：Shivendra Singh ; Ahmed Abu-Zaid ; Wenwei Lin 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：1
页码：1-38
DOI：10.1016/j.isci.2020.101996
语种：English
出版社：Elsevier
摘要：SummaryHistone 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.Graphical AbstractDisplay OmittedHighlights•Identification of geldanamycin/17-DMAG as histone lysine demethylase inhibitors•Geldanamycin/17-DMAG causes degradation of PAX3-FOXO1, an Hsp90 client•Geldanamycin/17-DMAG induces epigenetic changes and targets PAX3-FOXO1 pathway•17-DMAG alone or combined with chemotherapy show potency to PAX3-FOXO1 xenograftsMolecular Biology; Cancer; Omics