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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 2

Knockdown of HDAC1 reduces viability of hGSCs in a p53-dependent manner.

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Knockdown of HDAC1 reduces viability of hGSCs in a p53-dependent manner....
(A) Quantification of the percentage of viable p53-WT and p53-mutant hGSCs and 2 nontumorigenic cell lines (NHAs, ihNPCs) transduced with shHDAC1_A or shHDAC1_B, compared with control cells transduced with nontarget shRNA (shNT) (n = 3). (B and C) Immunofluorescence staining (B) and quantification (C) of Ki67-positive hGSCs after acute HDAC1 silencing (n = 3). (D and E) Immunofluorescence staining (D) and quantification (E) of cleaved caspase-3–positive cells after acute HDAC1 silencing (n = 3). (F) Quantification of the percentage of viable p53-WT hGSCs overexpressing p53-DN or EGFP after HDAC1 knockdown (n = 3). Schematic below illustrates how overexpression of a p53 mutant (p53-DN) affects p53 function. (G) Quantification of immunoblots for total and acetylated p53 (K382) after HDAC1 silencing (shH1_A, shHDAC1_A) in p53-WT BT145 (n = 3). Schematic below illustrates how HDAC1 opposes p53 activation through direct deacetylation. For each cell line, the data are compiled from at least 3 independent experiments for each shRNA. Error bars indicate SEM. **P < 0.01, ***P < 0.001, ****P < 0.0001. Original magnification, 20×; scale bars, 2 μm. P values were determined using the 2-way ANOVA with Tukey’s multiple comparisons test or unpaired 2-tailed t test. See also Supplemental Figure 2, Supplemental Figure 3, and Supplemental Tables 1 and 2.

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