Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG
Summary: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-04-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721003089 |
| _version_ | 1818657321011642368 |
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| author | Anahid Ehteda Sandy Simon Laura Franshaw Federico M. Giorgi Jie Liu Swapna Joshi Jourdin R.C. Rouaen Chi Nam Ignatius Pang Ruby Pandher Chelsea Mayoh Yujie Tang Aaminah Khan Caitlin Ung Ornella Tolhurst Anne Kankean Elisha Hayden Rebecca Lehmann Sylvie Shen Anjana Gopalakrishnan Peter Trebilcock Katerina Gurova Andrei V. Gudkov Murray D. Norris Michelle Haber Orazio Vittorio Maria Tsoli David S. Ziegler |
| author_facet | Anahid Ehteda Sandy Simon Laura Franshaw Federico M. Giorgi Jie Liu Swapna Joshi Jourdin R.C. Rouaen Chi Nam Ignatius Pang Ruby Pandher Chelsea Mayoh Yujie Tang Aaminah Khan Caitlin Ung Ornella Tolhurst Anne Kankean Elisha Hayden Rebecca Lehmann Sylvie Shen Anjana Gopalakrishnan Peter Trebilcock Katerina Gurova Andrei V. Gudkov Murray D. Norris Michelle Haber Orazio Vittorio Maria Tsoli David S. Ziegler |
| author_sort | Anahid Ehteda |
| collection | DOAJ |
| description | Summary: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG. |
| first_indexed | 2024-12-17T03:39:37Z |
| format | Article |
| id | doaj.art-f3c43c1ed6e44cbd8f4c250a0e00921a |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-17T03:39:37Z |
| publishDate | 2021-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f3c43c1ed6e44cbd8f4c250a0e00921a2022-12-21T22:05:03ZengElsevierCell Reports2211-12472021-04-01352108994Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPGAnahid Ehteda0Sandy Simon1Laura Franshaw2Federico M. Giorgi3Jie Liu4Swapna Joshi5Jourdin R.C. Rouaen6Chi Nam Ignatius Pang7Ruby Pandher8Chelsea Mayoh9Yujie Tang10Aaminah Khan11Caitlin Ung12Ornella Tolhurst13Anne Kankean14Elisha Hayden15Rebecca Lehmann16Sylvie Shen17Anjana Gopalakrishnan18Peter Trebilcock19Katerina Gurova20Andrei V. Gudkov21Murray D. Norris22Michelle Haber23Orazio Vittorio24Maria Tsoli25David S. Ziegler26Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaDepartment of Pharmacy and Biotechnology, University of Bologna, Bologna, ItalyChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaSchool of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, AustraliaState Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaDepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USADepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USAChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; Centre for Childhood Cancer Research, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, AustraliaChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia; Corresponding authorChildren’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia; Kid’s Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia; Corresponding authorSummary: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.http://www.sciencedirect.com/science/article/pii/S2211124721003089DIPGbrainstem gliomaH3K27Mfacilitates chromatin transcription complexHDACEZH2 |
| spellingShingle | Anahid Ehteda Sandy Simon Laura Franshaw Federico M. Giorgi Jie Liu Swapna Joshi Jourdin R.C. Rouaen Chi Nam Ignatius Pang Ruby Pandher Chelsea Mayoh Yujie Tang Aaminah Khan Caitlin Ung Ornella Tolhurst Anne Kankean Elisha Hayden Rebecca Lehmann Sylvie Shen Anjana Gopalakrishnan Peter Trebilcock Katerina Gurova Andrei V. Gudkov Murray D. Norris Michelle Haber Orazio Vittorio Maria Tsoli David S. Ziegler Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG Cell Reports DIPG brainstem glioma H3K27M facilitates chromatin transcription complex HDAC EZH2 |
| title | Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG |
| title_full | Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG |
| title_fullStr | Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG |
| title_full_unstemmed | Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG |
| title_short | Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG |
| title_sort | dual targeting of the epigenome via fact complex and histone deacetylase is a potent treatment strategy for dipg |
| topic | DIPG brainstem glioma H3K27M facilitates chromatin transcription complex HDAC EZH2 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721003089 |
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