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IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat

INTRODUCTION: A large subset of diffusely infiltrative gliomas contains a gain-of-function mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2(mut)) which produces 2-hydroxglutarate, an inhibitor of α-ketoglutarate-dependent DNA demethylases, thereby inducing widespread DNA and histone methylation....

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Autores principales: Sears, Thomas K., Horbinski, Craig M., Woolard, Kevin D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437887/
https://www.ncbi.nlm.nih.gov/pubmed/34424450
http://dx.doi.org/10.1007/s11060-021-03829-0
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author Sears, Thomas K.
Horbinski, Craig M.
Woolard, Kevin D.
author_facet Sears, Thomas K.
Horbinski, Craig M.
Woolard, Kevin D.
author_sort Sears, Thomas K.
collection PubMed
description INTRODUCTION: A large subset of diffusely infiltrative gliomas contains a gain-of-function mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2(mut)) which produces 2-hydroxglutarate, an inhibitor of α-ketoglutarate-dependent DNA demethylases, thereby inducing widespread DNA and histone methylation. Because histone deacetylase (HDAC) enzymes are localized to methylated chromatin via methyl-binding domain proteins, IDH1/2(mut) gliomas may be more dependent on HDAC activity, and therefore may be more sensitive to HDAC inhibitors. METHODS: Six cultured patient-derived glioma cell lines, IDH1(wt) (n = 3) and IDH1(mut) (n = 3), were treated with an FDA-approved HDAC inhibitor, panobinostat. Cellular cytotoxicity and proliferation assays were conducted by flow cytometry. Histone modifications and cell signaling pathways were assessed using immunoblot and/or ELISA. RESULTS: IDH1(mut) gliomas exhibited marked upregulation of genes associated with the HDAC activity. Glioma cell cultures bearing IDH1(mut) were significantly more sensitive to the cytotoxic and antiproliferative effects of panobinostat, compared to IDH1(wt) glioma cells. Panobinostat caused a greater increase in acetylation of the histone residues H3K14, H3K18, and H3K27 in IDH1(mut) glioma cells. Another HDAC inhibitor, valproic acid, was also more effective against IDH1(mut) glioma cells. CONCLUSION: These data suggest that IDH1(mut) gliomas may be preferentially sensitive to HDAC inhibitors. Further, IDH1(mut) glioma cultures showed enhanced accumulation of acetylated histone residues in response to panobinostat treatment, suggesting a direct epigenetic mechanism for this sensitivity. This provides a rationale for further exploration of HDAC inhibitors against IDH1(mut) gliomas. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-021-03829-0.
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spelling pubmed-84378872021-09-29 IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat Sears, Thomas K. Horbinski, Craig M. Woolard, Kevin D. J Neurooncol Laboratory Investigation INTRODUCTION: A large subset of diffusely infiltrative gliomas contains a gain-of-function mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2(mut)) which produces 2-hydroxglutarate, an inhibitor of α-ketoglutarate-dependent DNA demethylases, thereby inducing widespread DNA and histone methylation. Because histone deacetylase (HDAC) enzymes are localized to methylated chromatin via methyl-binding domain proteins, IDH1/2(mut) gliomas may be more dependent on HDAC activity, and therefore may be more sensitive to HDAC inhibitors. METHODS: Six cultured patient-derived glioma cell lines, IDH1(wt) (n = 3) and IDH1(mut) (n = 3), were treated with an FDA-approved HDAC inhibitor, panobinostat. Cellular cytotoxicity and proliferation assays were conducted by flow cytometry. Histone modifications and cell signaling pathways were assessed using immunoblot and/or ELISA. RESULTS: IDH1(mut) gliomas exhibited marked upregulation of genes associated with the HDAC activity. Glioma cell cultures bearing IDH1(mut) were significantly more sensitive to the cytotoxic and antiproliferative effects of panobinostat, compared to IDH1(wt) glioma cells. Panobinostat caused a greater increase in acetylation of the histone residues H3K14, H3K18, and H3K27 in IDH1(mut) glioma cells. Another HDAC inhibitor, valproic acid, was also more effective against IDH1(mut) glioma cells. CONCLUSION: These data suggest that IDH1(mut) gliomas may be preferentially sensitive to HDAC inhibitors. Further, IDH1(mut) glioma cultures showed enhanced accumulation of acetylated histone residues in response to panobinostat treatment, suggesting a direct epigenetic mechanism for this sensitivity. This provides a rationale for further exploration of HDAC inhibitors against IDH1(mut) gliomas. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-021-03829-0. Springer US 2021-08-23 2021 /pmc/articles/PMC8437887/ /pubmed/34424450 http://dx.doi.org/10.1007/s11060-021-03829-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Laboratory Investigation
Sears, Thomas K.
Horbinski, Craig M.
Woolard, Kevin D.
IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat
title IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat
title_full IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat
title_fullStr IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat
title_full_unstemmed IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat
title_short IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat
title_sort idh1 mutant glioma is preferentially sensitive to the hdac inhibitor panobinostat
topic Laboratory Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437887/
https://www.ncbi.nlm.nih.gov/pubmed/34424450
http://dx.doi.org/10.1007/s11060-021-03829-0
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