p63 supports aerobic respiration through hexokinase II
p63 supports aerobic respiration through hexokinase II
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DOI：
10.1073/pnas.1508871112
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发表时间：
2015-09-15
影响因子：
11.1
通讯作者：
Candi, Eleonora
中科院分区：
文献类型：
--
作者：
Viticchie, Guiditta;Agostini, Massimiliano;Candi, Eleonora
Short p63 isoform, Delta Np63, 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 Delta Np63 depletion in human keratinocytes impairs mitochondrial basal respiration and increases mitochondrial membrane polarization and intracellular reactive oxygen species. We show Delta Np63-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 Delta Np63 as a master regulator in epithelial cells of a combined subset of molecular mechanisms, including cellular energy metabolism and respiration. The Delta Np63-HK2 axis is also present in epithelial cancer cells, suggesting that Delta Np63 could participate in cancer metabolic reprogramming.
