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. [Display omitted] •MDM2 is recruited to chromatin independently of p53•Chromatin-bound MDM2 regulates amino acid metabolism and redox homeostasis•PKM2 modulates MDM2 phosphorylation and its recruitment to chromatin•Metabolic functions of MDM2 contribute to cancer cell proliferation Riscal et al. show that the proto-oncogene MDM2 is recruited to chromatin through direct binding to ATF4 but independently of its well-known partner, p53. Chromatin-bound MDM2 regulates a transcriptional program involved in amino acid metabolism and redox homeostasis that contributes to cancer cell proliferation and tumor growth.