Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53.
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.
IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298 Montpellier, France; INSERM, U1194, 34298 Montpellier, France; Université de Montpellier, 34298 Montpellier, France; Institut Régional du Cancer Montpellier, 34298 Montpellier, France.
Romain
R
Riscal
IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298 Montpellier, France; INSERM, U1194, 34298 Montpellier, France; Université de Montpellier, 34298 Montpellier, France; Institut Régional du Cancer Montpellier, 34298 Montpellier, France.
Emilie
E
Schrepfer
IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298 Montpellier, France; INSERM, U1194, 34298 Montpellier, France; Université de Montpellier, 34298 Montpellier, France; Institut Régional du Cancer Montpellier, 34298 Montpellier, France.
Giuseppe
G
Arena
IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298 Montpellier, France; INSERM, U1194, 34298 Montpellier, France; Université de Montpellier, 34298 Montpellier, France; Institut Régional du Cancer Montpellier, 34298 Montpellier, France.
Madi Y
MY
Cissé
INSA, UPS, INP, Université de Toulouse, 135 Avenue de Rangueil, 31 077 Toulouse, France; INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés, 31400 Toulouse, France; CNRS, UMR5504, 31400 Toulouse, France.
Floriant
F
Bellvert
INSA, UPS, INP, Université de Toulouse, 135 Avenue de Rangueil, 31 077 Toulouse, France; INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés, 31400 Toulouse, France; CNRS, UMR5504, 31400 Toulouse, France.
Maud
M
Heuillet
Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Florian
F
Rambow
Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128 Station Centre-Ville, Montreal, QC H3C 3J7, Canada.
Eric
E
Bonneil
Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, 31059 Toulouse, France; INSERM UMR 1037, CRCT, Université Paul Sabatier Toulouse-III, 31062 Toulouse, France.
Frédérique
F
Sabourdy
IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298 Montpellier, France; INSERM, U1194, 34298 Montpellier, France; Université de Montpellier, 34298 Montpellier, France; Institut Régional du Cancer Montpellier, 34298 Montpellier, France.
Charles
C
Vincent
IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298 Montpellier, France; INSERM, U1194, 34298 Montpellier, France; Université de Montpellier, 34298 Montpellier, France; Institut Régional du Cancer Montpellier, 34298 Montpellier, France.
Imade
I
Ait-Arsa
Laboratoire de Biochimie Métabolique, IFB, CHU Purpan, 31059 Toulouse, France; INSERM UMR 1037, CRCT, Université Paul Sabatier Toulouse-III, 31062 Toulouse, France.
Thierry
T
Levade
Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128 Station Centre-Ville, Montreal, QC H3C 3J7, Canada; Department of Chemistry, Université de Montréal, P.O. Box 6128 Station Centre-Ville, Montreal, QC H3C 3J7, Canada.
Pierre
P
Thibaut
Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Jean-Christophe
JC
Marine
INSA, UPS, INP, Université de Toulouse, 135 Avenue de Rangueil, 31 077 Toulouse, France; INRA, UMR792 Ingénierie des Systèmes Biologiques et des Procédés, 31400 Toulouse, France; CNRS, UMR5504, 31400 Toulouse, France.
Jean-Charles
JC
Portais
INSERM UMR 1037, CRCT, Université Paul Sabatier Toulouse-III, 31062 Toulouse, France.
Jean-Emmanuel
JE
Sarry
IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298 Montpellier, France; INSERM, U1194, 34298 Montpellier, France; Université de Montpellier, 34298 Montpellier, France; Institut Régional du Cancer Montpellier, 34298 Montpellier, France. Electronic address: laurent.lecam@inserm.fr.
Laurent
L
Le Cam
IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298 Montpellier, France; INSERM, U1194, 34298 Montpellier, France; Université de Montpellier, 34298 Montpellier, France; Institut Régional du Cancer Montpellier, 34298 Montpellier, France. Electronic address: laetitia.linares@inserm.fr.
Laetitia K
LK
Linares
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005998:Glycine / Q000378:metabolism; D045325:HCT116 Cells; D006706:Homeostasis; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012694:Serine / Q000378:metabolism*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
D051701:Activating Transcription Factor 4; D002352:Carrier Proteins; D002843:Chromatin; D005998:Glycine; D008565:Membrane Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D012694:Serine; D013963:Thyroid Hormones; D016159:Tumor Suppressor Protein p53; D000097810:Thyroid Hormone-Binding Proteins; C497109:ATF4 protein, human; C495901:TP53 protein, human; C497206:MDM2 protein, human