Stem-25. Hdac1 Is Essential for Glioma Stem Cell Survival

Abstract

OLIG2 is a central nervous system-specific transcription factor that is expressed in almost all diffuse gliomas. It is also one of the key core transcription factors that can reprogram differentiated glioma cells to highly tumorigenic glioma stem-like cells (GSCs). We have previously shown that expression of OLIG2 is critical for glioma growth both in a genetically relevant mouse model as well as in patient-derived xenograft models. Our work suggests that a small molecule inhibitor of OLIG2 could serve as a highly targeted therapy for high-grade glioma; however, transcription factors are generally very difficult to target because their interactions with DNA and co-regulatory proteins involve large and complex surface area contacts. Our laboratory has shown that OLIG2 functions are regulated through interactions with distinct co-regulator proteins in normal neural stem cells. However, there are currently no reports on interactors that promote the proto-oncogenic functions of OLIG2 in malignant glioma. In this study, we employed two independent proteomics screens identify tumor-specific, druggable OLIG2 co-regulators as possible surrogate targets to suppress OLIG2 function in glioma. These screens led to the identification of a novel OLIG2 partner protein: Histone Deacetylase 1 (HDAC1). We confirmed that this interaction occurs in both murine and human glioma models. Although HDACs are ubiquitously expressed and are known to be functionally redundant, we show that ablation of HDAC1 alone significantly decreases the stemness and proliferation capacity of patient-derived GSCs in a p53-dependent manner, while having a minimal impact on normal human neural stem cells and astrocytes. Furthermore, we demonstrate that knockdown of HDAC1, in combination with ionizing radiation treatment, significantly alters the growth pattern of intracranial tumors in vivo. We demonstrate that HDAC1 function is critical for GSC growth and provide a strong rationale for targeting the OLIG2-HDAC1 interaction in malignant glioma.

Comprehensive Analysis of the Differential Expression and Prognostic Value of Histone Deacetylases in Glioma

“…HDAC1 ablation significantly decreased stemness and proliferation in patient-derived GSCs in a p53-dependent manner. By contrast, it had only minimal impact on normal human neural stem cells and astrocytes ( Lo Cascio et al, 2019 ). HDAC1 knockdown inhibited the epithelial–mesenchymal transition transcription factors TWIST1 and SNAIL, downregulated the mesenchymal marker matrix metalloprotein-9, and upregulated the epithelial marker E-cadherin 34.…”

“…GO enrichment and KEGG pathway were analyzed with OmicShare Tools. Previous studies have evaluated the roles of certain HDAC family members in glioma (Lodrini et al, 2013;Wang et al, 2017;Lo Cascio et al, 2019;Song et al, 2020). A previous study has indicated that the NFAT2-HDAC1 pathway may maintain the malignant phenotype and promote mesenchymal transition in glioma stem-like cells (GSCs).…”