| Autor: |
Shivendra Singh, Ahmed Abu-Zaid, Wenwei Lin, Jonathan Low, Alireza Abdolvahabi, Hongjian Jin, Qiong Wu, Bailey Cooke, Jie Fang, John Bowling, Sivaraja Vaithiyalingam, Duane Currier, Mi-Kyung Yun, Dinesh M. Fernando, Julie Maier, Heather Tillman, Purva Bulsara, Zhaohua Lu, Sourav Das, Anang Shelat, Zhenmei Li, Brandon Young, Richard Lee, Zoran Rankovic, Andrew J. Murphy, Stephen W. White, Andrew M. Davidoff, Taosheng Chen, Jun Yang |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
iScience, Vol 24, Iss 1, Pp 101996- (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2589-0042 |
| DOI: |
10.1016/j.isci.2020.101996 |
| Popis: |
Summary: 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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