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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 4

HDAC1 knockdown reduces expression of key stemness and cell fate factors.

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HDAC1 knockdown reduces expression of key stemness and cell fate factor...
(A) Immunoblots showing increase in H3K4/19ac and H3K27ac after HDAC1 silencing in BT145 and BT187 (shH1_A, shHDAC1_A; shH1B, shHDAC1_B) (n = 3). (B) Representative immunoblots of p53-WT (BT145), p53-mutant (BT187) and p53-WT cells overexpressing p53-DN (BT145 + p53-DN) hGSCs after acute silencing of HDAC1 probed for various markers (n = 3). Black arrow indicates expression of WT EGFR. (C–E) Quantification of expression of proteins (normalized to Vinculin) after HDAC1 knockdown from immunoblots using p53-WT (C), p53-mutant (D), and p53-WT cells overexpressing p53-DN (E). For each cell line, the data are compiled from at least 3 independent experiments for each shRNA. Error bars indicate SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. P values were determined using the 2-way ANOVA with Tukey’s multiple comparisons test.

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