EPCO-68. CHD5 IS A TUMOR SUPPRESSOR IN GLIOBLASTOMA

Abstract Cancer arises from genetic and epigenetic alterations that reprogram gene expression networks, driving unchecked proliferation. Glioblastoma (GBM), the most common and lethal primary brain tumor, has a median survival of about one year and a dismal 5% five-year survival rate. Despite extensive research, effective treatments remain elusive, underscoring the need for a deeper understanding of GBM biology. Although several genetic alterations have been implicated in gliomagenesis, driving genetic factors responsible for GBM are still obscure, and how these genetic changes interact with epigenetic dysregulation is poorly understood. Here, we identify CHD5, a gene located in the frequently deleted 1p36 chromosomal region, as recurrently deleted in over 20% of GBM cases and further downregulated epigenetically. To investigate the role of CHD5 in gliomagenesis, we generated a glioma-prone mouse model carrying conditional alleles of Pten, Trp53, and Chd5, and employed engineered neural stem cells (NSCs)—a major GBM cell-of-origin—to induce tumor formation. Loss of Chd5 impaired NSC differentiation, enhanced proliferation, and drove in vivo gliomagenesis. Mechanistically, Chd5 forms a NuRD complex that binds the Myc promoter and super-enhancers to regulate its expression. Chd5 loss leads to chromatin accessibility changes, Myc upregulation, and aggressive tumor development. Importantly, reactivating CHD5 in human GBM xenografts significantly extended survival. These findings establish CHD5 as a tumor suppressor in gliomagenesis, offer therapeutic insights for cancers with 1p36 deletions, and present a robust NSC-based platform for functional genetic studies and modeling GBM pathogenesis.