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Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (<i>KDM5C</i>) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5C^High and KDM5C^Low, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (<i>BDNF</i>)—a negative KDM5C target—and a robust overexpression of hypoxia-inducible transcription factor-1A (<i>HIF1A</i>) gene, a <i>KDM5C</i> modulator. Additionally, a significant co-expression among the prognostic markers <i>HIF1A</i>, <i>Survivin</i>, and <i>p75</i> was observed. These results, corroborated by <i>KDM5C</i> overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher <i>KDM5C</i> and <i>HIF1A</i> levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High <i>NANOG</i> and <i>IL6</i> levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5C^High subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on <i>KDM5C</i> as a potential therapeutic target of the hypoxic microenvironment in GBM.