{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T15:05:12Z","timestamp":1789571112583,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"The Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["26K09870"],"award-info":[{"award-number":["26K09870"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"The Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["23K05094"],"award-info":[{"award-number":["23K05094"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"award":["26K09870"],"award-info":[{"award-number":["26K09870"]}],"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]},{"award":["23K05094"],"award-info":[{"award-number":["23K05094"]}],"id":[{"id":"https:\/\/ror.org\/048rj2z13","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epigenomes"],"abstract":"<jats:p>Background\/Objectives: Metabolic reprogramming is a hallmark of cancer and requires coordinated regulation of glycolysis and mitochondrial metabolism. The pyruvate dehydrogenase complex (PDC) links these pathways by catalyzing the conversion of pyruvate to acetyl-CoA, yet the epigenetic mechanisms regulating PDC expression remain poorly understood. We investigated whether the histone demethylase KDM4B regulates PDC expression and mitochondrial metabolism in cancer cells. Methods: Human colorectal carcinoma (HCT-116), cervical adenocarcinoma (HeLa), melanoma (G-361), and non-malignant human proximal tubule epithelial (HK-2) cells were analyzed using glucose-response assays, RNA sequencing, RT-qPCR, immunoblotting, metabolic assays, fluorescence imaging, and cell viability analyses. KDM4B was disrupted by small interfering RNA (siRNA) and the selective inhibitor NCGC00244536. Results: Glucose availability induced coordinated upregulation of the PDC subunits PDHA1, DLD, and DLAT and was associated with increased proliferation and KDM4B expression in cancer cells. Both genetic depletion and pharmacological inhibition of KDM4B suppressed PDC expression and increased the repressive histone mark H3K9me3. Exploratory RNA-seq analysis revealed coordinated metabolic transcriptional reprogramming characterized by induction of glycolytic genes and suppression of PDC, the tricarboxylic acid cycle, and electron transport chain genes, together with increased PDK1 and reduced PDP1 expression, consistent with impaired mitochondrial glucose oxidation. These changes were accompanied by reduced pyruvate dehydrogenase activity, extracellular pyruvate accumulation, ATP depletion, impaired glucose uptake, mitochondrial depolarization, caspase-3 activation, increased lactate dehydrogenase release, reduced viability, and diminished proliferative capacity. These effects were generally more pronounced in the cancer cell models than in HK-2 cells. Conclusions: Our findings identify KDM4B as a regulator associated with maintenance of PDC expression and mitochondrial glucose metabolism in cancer cells. KDM4B inhibition suppresses PDC abundance and activity and is accompanied by metabolic dysfunction, mitochondrial depolarization, and reduced cell survival. These findings support a model in which the KDM4B\u2013PDC axis may contribute to metabolic homeostasis and survival in cancer cells and suggest that this pathway may represent a potential therapeutic vulnerability.<\/jats:p>","DOI":"10.3390\/epigenomes10030059","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:50:27Z","timestamp":1789566627000},"page":"59","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["KDM4B Maintains Pyruvate Dehydrogenase Complex Expression to Support Mitochondrial Metabolism and Survival in Cancer Cells"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2677-7729","authenticated-orcid":false,"given":"Sachiko","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Iwate Medical University, Yahaba 028-3694, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6491-347X","authenticated-orcid":false,"given":"Arif Ul","family":"Hasan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Iwate Medical University, Yahaba 028-3694, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Mami","family":"Obara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Iwate Medical University, Yahaba 028-3694, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Eiichi","family":"Taira","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Iwate Medical University, Yahaba 028-3694, Japan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s40880-018-0302-3","article-title":"Metabolic Recoding of Epigenetics in Cancer","volume":"38","author":"Wang","year":"2018","journal-title":"Cancer Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-030-65768-0_1","article-title":"Glucose Metabolism in Cancer: The Warburg Effect and Beyond","volume":"1311","author":"Bose","year":"2021","journal-title":"Adv. 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