{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:43:22Z","timestamp":1789127002100,"version":"build-2803163510"},"reference-count":79,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Maria Rosaria Maglione Foundation Onlus","award":["MRM#2020"],"award-info":[{"award-number":["MRM#2020"]}]},{"name":"Maria Rosaria Maglione Foundation Onlus","award":["23453"],"award-info":[{"award-number":["23453"]}]},{"name":"My First AIRC Grant (MFAG) Programme","award":["MRM#2020"],"award-info":[{"award-number":["MRM#2020"]}]},{"name":"My First AIRC Grant (MFAG) Programme","award":["23453"],"award-info":[{"award-number":["23453"]}]},{"name":"SATIN-POR CAMPANIA FESR 2014\/2020","award":["MRM#2020"],"award-info":[{"award-number":["MRM#2020"]}]},{"name":"SATIN-POR CAMPANIA FESR 2014\/2020","award":["23453"],"award-info":[{"award-number":["23453"]}]},{"name":"Maria Rosaria Maglione Foundation Onlus","award":["MRM#2020"],"award-info":[{"award-number":["MRM#2020"]}]},{"name":"Maria Rosaria Maglione Foundation Onlus","award":["23453"],"award-info":[{"award-number":["23453"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 KDM5CHigh and KDM5CLow, displaying higher\/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)\u2014a negative KDM5C target\u2014and 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 KDM5CHigh 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.<\/jats:p>","DOI":"10.3390\/ijms231810250","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T20:52:51Z","timestamp":1662497571000},"page":"10250","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme"],"prefix":"10.3390","volume":"23","author":[{"given":"Denise","family":"Drongitis","sequence":"first","affiliation":[{"name":"Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy"},{"name":"Maria Rosaria Maglione Foundation Onlus, 80122 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Verrillo","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasqualino","family":"De Marinis","sequence":"additional","affiliation":[{"name":"A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Orabona","sequence":"additional","affiliation":[{"name":"A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Pathology, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnese","family":"Caiola","sequence":"additional","affiliation":[{"name":"A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Pathology, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacinto","family":"Turitto","sequence":"additional","affiliation":[{"name":"A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Oncology, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Alfieri","sequence":"additional","affiliation":[{"name":"A.O.R.N. S. Anna and S. 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Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-6933","authenticated-orcid":false,"given":"Valerio","family":"Costa","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1396-9673","authenticated-orcid":false,"given":"Maria Giuseppina","family":"Miano","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5484-1652","authenticated-orcid":false,"given":"Alberto","family":"de Bellis","sequence":"additional","affiliation":[{"name":"Maria Rosaria Maglione Foundation Onlus, 80122 Naples, Italy"},{"name":"A.O.R.N. S. Anna and S. Sebastiano Hospital, Division of Neurosurgery, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/B978-0-12-802997-8.00005-0","article-title":"Histologic classification of gliomas","volume":"134","author":"Perry","year":"2016","journal-title":"Handb. Clin. Neurol."},{"key":"ref_2","first-page":"3","article-title":"Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment","volume":"18","author":"Hanif","year":"2017","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Belisario, D.C., Kopecka, J., Pasino, M., Akman, M., De Smaele, E., Donadelli, M., and Riganti, C. (2020). Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance. 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