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Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):11577-82. doi: 10.1073/pnas.1508871112. Epub 2015 Aug 31.

p63 supports aerobic respiration through hexokinase II.

Author information

1
Department of Experimental Medicine and Surgery, University of "Tor Vergata", 00133 Rome, Italy;
2
Department of Experimental Medicine and Surgery, University of "Tor Vergata", 00133 Rome, Italy; Toxicology Unit, Medical Research Council, Leicester LE1 9HN, United Kingdom;
3
Department of Molecular Developmental Biology, Radboud University, 6525 GA Nijmegen, The Netherlands;
4
Department of Ecological and Biological Sciences, Tuscia University, 01100 Viterbo, Italy;
5
Toxicology Unit, Medical Research Council, Leicester LE1 9HN, United Kingdom;
6
Chanel Parfumes Beauté, F-92521 Neuilly-sur-Seine, France;
7
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.
8
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.

Abstract

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.

KEYWORDS:

HK2; keratinocytes; mitochondria; oxidative metabolism; p63

PMID:
26324887
PMCID:
PMC4577137
DOI:
10.1073/pnas.1508871112
[Indexed for MEDLINE]
Free PMC Article

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