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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.
Highlights
A well-regulated interplay between histone acetylation and deacetylation, mediated by histone acetyltransferases and histone deacetylases (HDACs), is essential for the dynamic fine-tuning of gene expression [1]
We compared HDAC1 and HDAC2 protein expression in gliomas using the Human Proteome Atlas and found that both were strongly expressed in most gliomas, HDAC1 expression is higher in GBM than in low-grade gliomas [32]
We found that expression of STAT3, TGFB2, MET, ICAM1, CSF1, ITGB5, BDNF, NRP1, and NRG5 was significantly induced after HDAC1 knockdown almost exclusively in p53 wild-type (p53-WT) but not p53-mutant human GSCs (hGSCs) (Figure 7A)
Summary
A well-regulated interplay between histone acetylation and deacetylation, mediated by histone acetyltransferases and histone deacetylases (HDACs), is essential for the dynamic fine-tuning of gene expression [1]. Systemic inhibition of HDACs with pharmacological inhibitors fails to provide significant therapeutic benefit in clinical trials for primary and recurrent GBM [4,5,6,7,8]. HDACi currently in clinical trials have poor brain penetration and a narrow therapeutic window due to their relatively low selectivity for individual HDAC isoforms [3, 7, 9,10,11]. Not all HDACs are expressed in GBM, and the specific functions of individual HDAC isoforms in these tumors are not well understood [12]. There is a need to dissect the functional importance and requirement for individual HDACs in GBM, especially the therapy-resistant glioma stem cells (GSCs), to provide a rationale for the development of isoform-selective HDACi
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