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Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):11004-9. doi: 10.1073/pnas.1602751113. Epub 2016 Sep 12.

E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.

Author information

1
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France;
2
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Réseau d'Histologie Expérimentale de Montpellier, BioCampus, CNRS-UMS3426, F-34094 Montpellier, France;
3
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France;
4
Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland;
5
Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France; Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cite, UMR7216 CNRS, Paris 75013, France;
6
University of Montpellier, Montpellier F-34090, France; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France;
7
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Réseau d'Histologie Expérimentale de Montpellier, BioCampus, CNRS-UMS3426, F-34094 Montpellier, France;
8
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France;
9
Institut de la Clinique de la Souris-Mouse Clinical Institute, PHENOMIN, CNRS-UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France.
10
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France; matthieu.lacroix@inserm.fr laurent.lecam@inserm.fr.

Abstract

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of epidermal stem cell (ESC) maintenance. Here, we found that E4F1 transcriptionally regulates a metabolic program involved in pyruvate metabolism that is required to maintain skin homeostasis. E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetyltransferase (Dlat), a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase (PDH) complex. Accordingly, E4f1 knock-out (KO) keratinocytes exhibited impaired PDH activity and a redirection of the glycolytic flux toward lactate production. The metabolic reprogramming of E4f1 KO keratinocytes associated with remodeling of their microenvironment and alterations of the basement membrane, led to ESC mislocalization and exhaustion of the ESC pool. ShRNA-mediated depletion of Dlat in primary keratinocytes recapitulated defects observed upon E4f1 inactivation, including increased lactate secretion, enhanced activity of extracellular matrix remodeling enzymes, and impaired clonogenic potential. Altogether, our data reveal a central role for Dlat in the metabolic program regulated by E4F1 in basal keratinocytes and illustrate the importance of PDH activity in skin homeostasis.

KEYWORDS:

E4F1; PDH; pyruvate; skin; stem cell

PMID:
27621431
PMCID:
PMC5047149
DOI:
10.1073/pnas.1602751113
[Indexed for MEDLINE]
Free PMC Article

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