iScience (Jan 2021)
17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma
- 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
Affiliations
- Shivendra Singh
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA
- Ahmed Abu-Zaid
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA
- Wenwei Lin
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Jonathan Low
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Alireza Abdolvahabi
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Hongjian Jin
- Center for Applied Bioinformatics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Qiong Wu
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA
- Bailey Cooke
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA
- Jie Fang
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA
- John Bowling
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Sivaraja Vaithiyalingam
- Protein Technologies Center, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Department of Structural Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Duane Currier
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Mi-Kyung Yun
- Department of Structural Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Dinesh M. Fernando
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Julie Maier
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Heather Tillman
- Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Purva Bulsara
- Department of Biostatistics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Zhaohua Lu
- Department of Biostatistics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Sourav Das
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Anang Shelat
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Zhenmei Li
- Department of Structural Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Brandon Young
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Richard Lee
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Zoran Rankovic
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Andrew J. Murphy
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA
- Stephen W. White
- Department of Structural Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Andrew M. Davidoff
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA
- Taosheng Chen
- Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Corresponding author
- Jun Yang
- Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA; Corresponding author
- Journal volume & issue
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Vol. 24,
no. 1
p. 101996
Abstract
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.
