p63 supports aerobic respiration through hexokinase II.
Short p63 isoform, ΔNp63, is crucial for epidermis formation, and it plays a pivotal role in controlling the turnover of basal keratinocytes by regulating the expression of a subset of genes involved in cell cycle and cell adhesion programs. The glycolytic enzyme hexokinase 2 (HK2) represents the first step of glucose utilization in cells. The family of HKs has four isoforms that differ mainly in their tissue and subcellular distribution. The preferential mitochondrial localization of HK2 at voltage-dependent anion channels provides access to ATP generated by oxidative phosphorylation and generates an ADP/ATP recycling mechanism to maintain high respiration rates and low electron leak. Here, we report that ΔNp63 depletion in human keratinocytes impairs mitochondrial basal respiration and increases mitochondrial membrane polarization and intracellular reactive oxygen species. We show ΔNp63-dependent regulation of HK2 expression, and we use ChIP, validated by p63-Chip sequencing genomewide profiling analysis, and luciferase assays to demonstrate the presence of one p63-specific responsive element within the 15th intronic region of the HK2 gene, providing evidence of a direct interaction. Our data support the notion of ΔNp63 as a master regulator in epithelial cells of a combined subset of molecular mechanisms, including cellular energy metabolism and respiration. The ΔNp63-HK2 axis is also present in epithelial cancer cells, suggesting that ΔNp63 could participate in cancer metabolic reprogramming.
Department of Experimental Medicine and Surgery, University of "Tor Vergata", 00133 Rome, Italy;
Guiditta
G
Viticchiè
Department of Experimental Medicine and Surgery, University of "Tor Vergata", 00133 Rome, Italy; Toxicology Unit, Medical Research Council, Leicester LE1 9HN, United Kingdom;
Massimiliano
M
Agostini
Department of Experimental Medicine and Surgery, University of "Tor Vergata", 00133 Rome, Italy;
Anna Maria
AM
Lena
Department of Experimental Medicine and Surgery, University of "Tor Vergata", 00133 Rome, Italy; Toxicology Unit, Medical Research Council, Leicester LE1 9HN, United Kingdom;
Mara
M
Mancini
Department of Molecular Developmental Biology, Radboud University, 6525 GA Nijmegen, The Netherlands;
Huiqing
H
Zhou
Department of Ecological and Biological Sciences, Tuscia University, 01100 Viterbo, Italy;
Lello
L
Zolla
Toxicology Unit, Medical Research Council, Leicester LE1 9HN, United Kingdom;
David
D
Dinsdale
Chanel Parfumes Beauté, F-92521 Neuilly-sur-Seine, France;
Gaelle
G
Saintigny
Department of Experimental Medicine and Surgery, University of "Tor Vergata", 00133 Rome, Italy; Toxicology Unit, Medical Research Council, Leicester LE1 9HN, United Kingdom; candi@uniroma2.it gm89@le.ac.uk.
Gerry
G
Melino
Department of Experimental Medicine and Surgery, University of "Tor Vergata", 00133 Rome, Italy; Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, 00167 Rome, Italy candi@uniroma2.it gm89@le.ac.uk.
Eleonora
E
Candi
D000818:Animals; D049109:Cell Proliferation; D002469:Cell Separation; D005434:Flow Cytometry; D020868:Gene Silencing; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010101:Oxygen Consumption; D010641:Phenotype; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D006861:Hydrogen Peroxide; D006593:Hexokinase; D010100:Oxygen
HK2; keratinocytes; mitochondria; oxidative metabolism; p63