P63 supports aerobic respiration through hexokinase II

Guiditta Viticchiè, Massimiliano Agostini, Anna Maria Lena, Mara Mancini, Huiqing Zhou, Lello Zolla, David Dinsdale, Gaelle Saintigny, Gerry Melino, Eleonora Candi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)11577-11582
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number37
DOIs
Publication statusPublished - Sep 15 2015

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Hexokinase
Respiration
Keratinocytes
Voltage-Dependent Anion Channel 2
Protein Isoforms
Adenosine Triphosphate
Epithelial Cells
Oxidative Phosphorylation
Recycling
Mitochondrial Membranes
Tissue Distribution
Respiratory Rate
Luciferases
Epidermis
Cell Adhesion
Adenosine Diphosphate
Energy Metabolism
Genes
Reactive Oxygen Species
Neoplasms

Keywords

  • HK2
  • Keratinocytes
  • Mitochondria
  • Oxidative metabolism
  • P63

ASJC Scopus subject areas

  • General

Cite this

P63 supports aerobic respiration through hexokinase II. / Viticchiè, Guiditta; Agostini, Massimiliano; Lena, Anna Maria; Mancini, Mara; Zhou, Huiqing; Zolla, Lello; Dinsdale, David; Saintigny, Gaelle; Melino, Gerry; Candi, Eleonora.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 37, 15.09.2015, p. 11577-11582.

Research output: Contribution to journalArticle

Viticchiè, G, Agostini, M, Lena, AM, Mancini, M, Zhou, H, Zolla, L, Dinsdale, D, Saintigny, G, Melino, G & Candi, E 2015, 'P63 supports aerobic respiration through hexokinase II', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 37, pp. 11577-11582. https://doi.org/10.1073/pnas.1508871112
Viticchiè, Guiditta ; Agostini, Massimiliano ; Lena, Anna Maria ; Mancini, Mara ; Zhou, Huiqing ; Zolla, Lello ; Dinsdale, David ; Saintigny, Gaelle ; Melino, Gerry ; Candi, Eleonora. / P63 supports aerobic respiration through hexokinase II. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 37. pp. 11577-11582.
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