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Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
Costanza Lo Cascio, … , Christopher L. Plaisier, Shwetal Mehta
Costanza Lo Cascio, … , Christopher L. Plaisier, Shwetal Mehta
Published September 8, 2021
Citation Information: JCI Insight. 2021;6(17):e149232. https://doi.org/10.1172/jci.insight.149232.
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Research Article Oncology Stem cells

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

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Abstract

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.

Authors

Costanza Lo Cascio, James B. McNamara, Ernesto L. Melendez, Erika M. Lewis, Matthew E. Dufault, Nader Sanai, Christopher L. Plaisier, Shwetal Mehta

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Figure 1

HDAC1 expression levels in GBM.

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HDAC1 expression levels in GBM.
(A) HDAC1 (B) and HDAC2 expression leve...
(A) HDAC1 (B) and HDAC2 expression levels across various grades of gliomas (OL, oligodendroglioma; OA, oligoastrocytoma; A, astrocytoma; GBM, glioblastoma) within the TCGA, CCGA, and REMBRANDT databases. HDAC1, but not HDAC2, expression significantly increases with malignancy; Tukey’s post hoc test. (C) HDAC1 expression levels across the 3 GBM molecular subtypes (CL, classical; MES, mesenchymal; PN, proneural). (D) Kaplan-Meier analysis stratifying glioma patients with HDAC1 high and low expression within the TCGA, CCGA, and Rembrandt databases; log-rank test. (E) Immunoblot showing basal levels of HDAC1 and HDAC2 in p53-WT hGSCs (BT145, BT286, GB3, and GB71) and p53-mutant hGSCs (BT187, BT70, GB82, and GB84) (n = 3). (F) Immunoblot showing basal levels of HDAC1 and HDAC2 in nontumorigenic normal human astrocytes (NHAs) and induced pluripotent stem cell–derived (iPSC-derived) human neural progenitor cells (ihNPCs) alongside 2 hGSC lines (n = 3). The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. *P < 0.05; **P < 0.01; ***P < 0.001. See also Supplemental Figure 1.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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