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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 6

HDAC1 knockdown upregulates cell migration programs and results in more invasive tumors.

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HDAC1 knockdown upregulates cell migration programs and results in more...
(A) Venn diagram illustrating the overlap between the significantly up- and downregulated genes between GSC cell lines after shHDAC1 knockdown. (B) Log2 fold change of gene expression after shHDAC1 knockdown in p53-WT hGSCs BT145 (red) and GB3 (green) hGSCs (adjusted P ≤ 0.05). (C) Negative log10 P value for functional enrichment of relevant Gene Ontology Biological Process (GO BP) terms for genes with significantly increased gene expression after shHDAC1 knockdown in BT145 (red) and/or GB3 (green) tumorigenic cell lines. (D) BT145 and GB3 specific regulatory network for upregulated genes following HDAC1 knockdown. Red triangles are transcription factor regulators and parallelograms are hallmarks of cancer. Edges indicate association between the target genes of the regulator and a hallmark of cancer and are colored according to its corresponding hallmark. For each cell line, the data are compiled from 3 independent experiments. (E and F) Stitched whole-brain images of DAPI (blue) and GFP-positive engrafted tumor cells (green) in (E) shNT and (F) shHDAC1 BT145 brain tissue 7 weeks postengraftment. GFP expression reveals HDAC1-deficient tumors are more invasive than control shNT tumors. Original magnification, 10×; scale bars, 1 mm. See also Supplemental Figure 6.

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