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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 3

HDAC1 function is nonredundant in hGSCs and is not compensated for by its paralogue HDAC2.

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HDAC1 function is nonredundant in hGSCs and is not compensated for by it...
(A) Log2 fold change of differential expression for the 11 HDACs (HDAC1–11) after short hairpin HDAC (shHDAC1) knockdown in 2 nontumorigenic (ihNPC and NHA) and 3 hGSC (BT145, GB3, BT187) cell lines. Blue bolded boxes indicate significant differential expression (adjusted P ≤ 0.05). (B) Representative immunoblot showing protein levels of HDAC1 and HDAC2 after acute HDAC2 knockdown (shHDAC2) in p53-WT (BT145) and p53-mutant (BT187) hGSCs. (C) Quantification of expression of HDAC2 and HDAC1 protein (normalized to Vinculin) after HDAC2 knockdown in BT145 (n = 4) and BT187 (n = 3). (D) Quantification of the percentage of viable hGSCs (BT145 and BT187) 7 days after HDAC2 knockdown, relative to shNT controls (n = 3). (E) Immunoblot comparing levels of acetylated p53 (K382) and HDAC1 and HDAC2 protein after HDAC1 and HDAC2 silencing in p53-WT hGSCs (BT145). 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 < 0.0001. P values were calculated using unpaired 2-tailed t test. See also Supplemental Figure 4.

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ISSN 2379-3708

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