17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma
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 ide...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-01-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220311937 |
| _version_ | 1829484629464186880 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Shivendra Singh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T22:30:07Z |
| format | Article |
| id | doaj.art-06c582be98bb44abbf752e112dc13534 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-14T22:30:07Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-06c582be98bb44abbf752e112dc135342022-12-21T22:45:16ZengElsevieriScience2589-00422021-01-0124110199617-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcomaShivendra Singh0Ahmed Abu-Zaid1Wenwei Lin2Jonathan Low3Alireza Abdolvahabi4Hongjian Jin5Qiong Wu6Bailey Cooke7Jie Fang8John Bowling9Sivaraja Vaithiyalingam10Duane Currier11Mi-Kyung Yun12Dinesh M. Fernando13Julie Maier14Heather Tillman15Purva Bulsara16Zhaohua Lu17Sourav Das18Anang Shelat19Zhenmei Li20Brandon Young21Richard Lee22Zoran Rankovic23Andrew J. Murphy24Stephen W. White25Andrew M. Davidoff26Taosheng Chen27Jun Yang28Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USADepartment of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USACenter for Applied Bioinformatics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USADepartment of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USADepartment of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USAProtein 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, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Structural Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Pathology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Biostatistics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Biostatistics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Structural Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USADepartment of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USADepartment 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, USADepartment of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USADepartment of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Corresponding authorDepartment of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis TN 38105, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004220311937Molecular BiologyCancerOmics |
| spellingShingle | 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 17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma iScience Molecular Biology Cancer Omics |
| title | 17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma |
| title_full | 17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma |
| title_fullStr | 17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma |
| title_full_unstemmed | 17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma |
| title_short | 17-DMAG dually inhibits Hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma |
| title_sort | 17 dmag dually inhibits hsp90 and histone lysine demethylases in alveolar rhabdomyosarcoma |
| topic | Molecular Biology Cancer Omics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220311937 |
| work_keys_str_mv | AT shivendrasingh 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT ahmedabuzaid 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT wenweilin 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT jonathanlow 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT alirezaabdolvahabi 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT hongjianjin 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT qiongwu 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT baileycooke 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT jiefang 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT johnbowling 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT sivarajavaithiyalingam 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT duanecurrier 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT mikyungyun 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT dineshmfernando 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT juliemaier 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT heathertillman 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT purvabulsara 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT zhaohualu 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT souravdas 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT anangshelat 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT zhenmeili 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT brandonyoung 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT richardlee 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT zoranrankovic 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT andrewjmurphy 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT stephenwwhite 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT andrewmdavidoff 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT taoshengchen 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma AT junyang 17dmagduallyinhibitshsp90andhistonelysinedemethylasesinalveolarrhabdomyosarcoma |