4.7 Article

The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme

Journal

Publisher

MDPI
DOI: 10.3390/ijms231810250

Keywords

glioblastoma multiforme; KDM5C; 5-aminolevulinic acid fluorescence-guided surgery (5-ALA FGS); HIF1A-KDM5C axis; GBM with epilepsy; hypoxic microenvironment

Funding

  1. Maria Rosaria Maglione Foundation Onlus grant [2020]
  2. My First AIRC Grant (MFAG) Programme [23453]
  3. SATIN-POR CAMPANIA FESR 2014/2020
  4. Maria Rosaria Maglione Foundation Onlus

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This study highlights the role of chromatin remodeling gene KDM5C in Glioblastoma multiforme (GBM) and suggests HIF1A-KDM5C axis as a potential therapeutic target for the hypoxic microenvironment in GBM. The study provides extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets, to show the contribution of KDM5C in GBM.
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 (KDM5C) 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 (BDNF)-a negative KDM5C target-and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C 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 KDM5C and HIF1A 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 NANOG and IL6 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 KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.

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