Energy Metabolism Rewiring Precedes UVB-Induced Primary Skin Tumor Formation

Publication date: 19 June 2018
Source:Cell Reports, Volume 23, Issue 12
Author(s): Mohsen Hosseini, Léa Dousset, Walid Mahfouf, Martin Serrano-Sanchez, Isabelle Redonnet-Vernhet, Samir Mesli, Zeinab Kasraian, Emilie Obre, Marc Bonneu, Stephane Claverol, Marija Vlaski, Zoran Ivanovic, Walid Rachidi, Thierry Douki, Alain Taieb, Anne-Karine Bouzier-Sore, Rodrigue Rossignol, Hamid Reza Rezvani
Although growing evidence indicates that bioenergetic metabolism plays an important role in the progression of tumorigenesis, little information is available on the contribution of reprogramming of energy metabolism in cancer initiation. By applying a quantitative proteomic approach and targeted metabolomics, we find that specific metabolic modifications precede primary skin tumor formation. Using a multistage model of ultraviolet B (UVB) radiation-induced skin cancer, we show that glycolysis, tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation are decreased at a very early stage of photocarcinogenesis, while the distal part of the electron transport chain (ETC) is upregulated. Reductive glutamine metabolism and the activity of dihydroorotate dehydrogenase (DHODH) are both necessary for maintaining high ETC. Mice with decreased DHODH activity or impaired ETC failed to develop pre-malignant and malignant lesions. DHODH activity represents a major link between DNA repair efficiency and bioenergetic patterning during skin carcinogenesis.

Graphical abstract

Teaser

Hosseini et al. show that specific metabolic modifications occur at a very early stage of photocarcinogenesis. Those modifications ensure the coordination of ATP generation, persistent nucleotide biosynthesis and repair of DNA damage, which all play an important role in defining of epidermal cell fate.


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