Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
Open accessAbstract
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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In GBM, silencing of HDAC1, but not HDAC2, profoundly affects proliferation of glioma stem cells by reactivating TP53 activities.
“In GBM, silencing of HDAC1, but not HDAC2, profoundly affects proliferation of glioma stem cells by reactivating TP53 activities.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Lo Cascio et al., 2021
When the same GBM cells are transplanted in a different microenvironment in vivo, the absence of HDAC1 leads to a more aggressive/invasive phenotype through activation of STAT3.
“However, when the same GBM cells are transplanted in a different microenvironment in vivo, the absence of HDAC1 leads to a more aggressive/ invasive phenotype through activation of STAT3 (Lo Cascio et al., 2021).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Lo Cascio et al., 2021
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References 104 · Cited by 33
Research works printed but not linked: 1
- [35]McLendon R et al Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 2008 455 7216 1061 1068 10.1038/nature07385 18772890 PMC2671642 · DOI · Paper page
- Authors
- Lo Cascio, C., McNamara, J. B., Melendez, E. L., Lewis, E. M., Dufault, M. E., Sanai, N., Plaisier, C. L., & Mehta, S.
- Affiliations
- Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, Arizona, USA.
- Barrow Neurological Institute (US)
- Arizona State University (US)
- Corresponding author
- Mehta, Shwetal
- ORCID
- Venue
- JCI Insight
- Published
- 2021-09-08
- Volume
- 6
- Issue
- 17
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC8492336
- OpenAlex
- W3197017270
- Cited by
- 33
- References
- 104
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 5 · 2023: 8 · 2022: 2 · 2021: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (NS088648A, CA211015)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- HDAC1, HDAC2, glioma stem cells, glioblastoma, histone deacetylase, p53, epigenetic regulation, compensatory pathways, combination therapy, tumor growth inhibition
- MeSH terms
- DNA, Neoplasm, Glioma, Humans, Mutation, Tumor Cells, Cultured, Neoplastic Stem Cells, Apoptosis, Protein Isoforms, Gene Expression Profiling, Histone Deacetylase 1
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