STEM-19. NON-REDUNDANT, ISOFORM-SPECIFIC ROLES OF HDAC1 IN THE REGULATION OF THE GLIOMA STEM CELL PHENOTYPE

Abstract

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. There is a temporal and cell-type specific requirement of HDAC1 and 2 during normal brain development, with HDAC2 being indispensable in neural stem cells. Here, we specifically investigated the functional importance of HDAC1 in glioma stem cells, an HDAC isoform whose expression increases with brain tumor grade and is correlated with decreased survival. Using cell-based and biochemical assays, transcriptomic analyses and patient-derived xenograft models, we report that knockdown of HDAC1 alone has profound effects on the glioma stem cell (GSC) phenotype and survival in a p53-dependent manner. HDAC1 is the essential class I deacetylase in glioma stem cells, and its loss is not compensated for by its paralogue HDAC2 or other HDACs. Loss of HDAC1 expression significantly suppresses viability of GSCs harboring functional p53, and that HDAC2 expression is completely dispensable in GSCs. In addition, HDAC1 silencing but not HDAC2, stabilizes and acetylates p53 in GSCs, resulting in upregulation of key p53 target genes and induction of programmed cell death. Furthermore, ablation of HDAC1 function alone results in histone hyperacetylation and a collapse of the stemness state in GSCs. We demonstrate significant 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 HDAC inhibitor drugs.