Chromatin-Bound MDM2 regulates serine metabolism and redox homeostasis independently of p53

Romain Riscal (1, 2) , Emilie Schrepfer (1, 2) , Giuseppe Arena (1, 2) , Madi Y. Cisse (1, 2) , Floriant Bellvert (3, 4) , Maud Heuillet (5) , Florian Rambow , Eric Bonneil (6) , Frederique Sabourdy (7, 8, 9) , Charles Vincent (1, 2) , Imade Ait-Arsa (1, 2) , Thierry Levade (7, 8, 9) , Pierre Thibaut (6, 10) , Jean-Christophe Marine (11, 12) , Jean-Charles Portais (5) , Jean-Emmanuel Sarry (8, 9) , Laurent Le Cam (1, 2) , Laetitia K. Linares (1, 2)

1 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
2 UM - Université de Montpellier
3 TBI - Toulouse Biotechnology Institute
4 TBI-MetaToul - MetaToul FluxoMet
5 LISBP - Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés
6 IRIC - Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal]
7 Laboratoire de Biochimie Métabolique
8 CRCT - Centre de Recherches en Cancérologie de Toulouse
9 UT - Université de Toulouse
10 Department of Chemistry
11 Laboratory for Molecular Cancer Biology, Center for Human Genetic
12 Laboratory for Molecular Cancer Biology, Center for the Biology of Disease

The mouse double minute 2 (MDM2) oncoprotein is recognized as a major negative regulator of the p53 tumor suppressor, but growing evidence indicates that its oncogenic activities extend beyond p53. Here, we show that MDM2 is recruited to chromatin independently of p53 to regulate a transcriptional program implicated in amino acid metabolism and redox homeostasis. Identification of MDM2 target genes at the whole-genome level highlights an important role for ATF3/4 transcription factors in tethering MDM2 to chromatin. MDM2 recruitment to chromatin is a tightly regulated process that occurs during oxidative stress and serine/glycine deprivation and is modulated by the pyruvate kinase M2 (PKM2) metabolic enzyme. Depletion of endogenous MDM2 in p53-deficient cells impairs serine/glycine metabolism, the NAD(+)/NADH ratio, and glutathione (GSH) recycling, impacting their redox state and tumorigenic potential. Collectively, our data illustrate a previously unsuspected function of chromatin-bound MDM2 in cancer cell metabolism.

Mots clés: pyruvate-kinase m2; activating transcription factor-3; cancer-cell survival; embryonic lethality; mdm2-deficient mice; tumor suppression; synthesis pathway; glycine; proliferation; overexpression

Domaines: Sciences du Vivant [q-bio]

Romain Riscal, Emilie Schrepfer, Giuseppe Arena, Madi Y. Cisse, Floriant Bellvert, et al.. Chromatin-Bound MDM2 regulates serine metabolism and redox homeostasis independently of p53. Molecular Cell, 2016, 62 (6), pp.890-902. ⟨10.1016/j.molcel.2016.04.033⟩. ⟨hal-01886397⟩