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Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells

Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the histone deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant...

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Autores principales: Lo Cascio, Costanza, McNamara, James B., Melendez, Ernesto L., Lewis, Erika M., Dufault, Matthew E., Sanai, Nader, Plaisier, Christopher L., Mehta, Shwetal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492336/
https://www.ncbi.nlm.nih.gov/pubmed/34494550
http://dx.doi.org/10.1172/jci.insight.149232
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author Lo Cascio, Costanza
McNamara, James B.
Melendez, Ernesto L.
Lewis, Erika M.
Dufault, Matthew E.
Sanai, Nader
Plaisier, Christopher L.
Mehta, Shwetal
author_facet Lo Cascio, Costanza
McNamara, James B.
Melendez, Ernesto L.
Lewis, Erika M.
Dufault, Matthew E.
Sanai, Nader
Plaisier, Christopher L.
Mehta, Shwetal
author_sort Lo Cascio, Costanza
collection PubMed
description Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the histone deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant functions and common substrates, the unique isoform-specific roles of different HDACs in GBM remain unclear. In neural stem cells, HDAC2 is the indispensable deacetylase to ensure normal brain development and survival in the absence of HDAC1. Surprisingly, we find that HDAC1 is the essential class I deacetylase in glioma stem cells, and its loss is not compensated for by HDAC2. Using cell-based and biochemical assays, transcriptomic analyses, and patient-derived xenograft models, we find that knockdown of HDAC1 alone has profound effects on the glioma stem cell phenotype in a p53-dependent manner. We demonstrate marked suppression in tumor growth upon targeting of HDAC1 and identify compensatory pathways that provide insights into combination therapies for GBM. Our study highlights the importance of HDAC1 in GBM and the need to develop isoform-specific drugs.
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spelling pubmed-84923362021-10-07 Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells Lo Cascio, Costanza McNamara, James B. Melendez, Ernesto L. Lewis, Erika M. Dufault, Matthew E. Sanai, Nader Plaisier, Christopher L. Mehta, Shwetal JCI Insight Research Article Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the histone deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant functions and common substrates, the unique isoform-specific roles of different HDACs in GBM remain unclear. In neural stem cells, HDAC2 is the indispensable deacetylase to ensure normal brain development and survival in the absence of HDAC1. Surprisingly, we find that HDAC1 is the essential class I deacetylase in glioma stem cells, and its loss is not compensated for by HDAC2. Using cell-based and biochemical assays, transcriptomic analyses, and patient-derived xenograft models, we find that knockdown of HDAC1 alone has profound effects on the glioma stem cell phenotype in a p53-dependent manner. We demonstrate marked suppression in tumor growth upon targeting of HDAC1 and identify compensatory pathways that provide insights into combination therapies for GBM. Our study highlights the importance of HDAC1 in GBM and the need to develop isoform-specific drugs. American Society for Clinical Investigation 2021-09-08 /pmc/articles/PMC8492336/ /pubmed/34494550 http://dx.doi.org/10.1172/jci.insight.149232 Text en © 2021 Lo Cascio et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Lo Cascio, Costanza
McNamara, James B.
Melendez, Ernesto L.
Lewis, Erika M.
Dufault, Matthew E.
Sanai, Nader
Plaisier, Christopher L.
Mehta, Shwetal
Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
title Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
title_full Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
title_fullStr Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
title_full_unstemmed Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
title_short Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
title_sort nonredundant, isoform-specific roles of hdac1 in glioma stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492336/
https://www.ncbi.nlm.nih.gov/pubmed/34494550
http://dx.doi.org/10.1172/jci.insight.149232
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