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

doi:10.1016/j.isci.2020.101996

17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma

iScience. 2020 Dec 28;24(1):101996. doi: 10.1016/j.isci.2020.101996. eCollection 2021 Jan 22.

Authors

Shivendra Singh¹, Ahmed Abu-Zaid¹, Wenwei Lin², Jonathan Low², Alireza Abdolvahabi², Hongjian Jin³, Qiong Wu¹, Bailey Cooke¹, Jie Fang¹, John Bowling², Sivaraja Vaithiyalingam^{4

5}, Duane Currier², Mi-Kyung Yun⁵, Dinesh M Fernando², Julie Maier², Heather Tillman⁶, Purva Bulsara⁷, Zhaohua Lu⁷, Sourav Das², Anang Shelat², Zhenmei Li⁵, Brandon Young², Richard Lee², Zoran Rankovic², Andrew J Murphy¹, Stephen W White^{5

8}, Andrew M Davidoff¹, Taosheng Chen², Jun Yang¹

Affiliations

¹ Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA.
² Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
³ Center for Applied Bioinformatics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
⁴ Protein Technologies Center, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
⁵ Department of Structural Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
⁶ Department of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
⁷ Department of Biostatistics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
⁸ Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Abstract

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.

Keywords: Cancer; Molecular Biology; Omics.

Abstract

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