Dynamic Regulation of ME1 Phosphorylation and Acetylation Affects Lipid Metabolism and Colorectal Tumorigenesis

• DOI: 10.1016/j.molcel.2019.10.015
• Publication Date: 2019-11-14T15:33:11Z
• Authors: Yahui Zhu; Li Gu; Xi Lin; Cheng Liu; Bingjun Lu; Kaisa Cui; Feng Zhou; Qiu Zhao; Edward V. Prochownik; Chengpeng Fan; Youjun Li
• Keywords: Male; Transcriptional Activation; 0303 health sciences; Carcinogenesis; Acetylation; HCT116 Cells; Lipid Metabolism; Up-Regulation; Mice, Inbred C57BL; Mice; 03 medical and health sciences; HEK293 Cells; Cell Line, Tumor; Phosphoprotein Phosphatases; Animals; Humans; Female; Acetyl-CoA C-Acetyltransferase; Phosphorylation; Colorectal Neoplasms; HT29 Cells; NADP

PGAM5 is a mitochondrial serine/threonine phosphatase that regulates multiple metabolic pathways and contributes to tumorigenesis in a poorly understood manner. We show here that PGAM5 inhibition attenuates lipid metabolism and colorectal tumorigenesis in mice. PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. ME1 also promotes nicotinamide adenine dinucleotide phosphate (NADPH) production, lipogenesis, and colorectal cancers in which ME1 transcripts are upregulated and ME1 protein is hypophosphorylated at S336 and hyperacetylated at K337. PGAM5 and ME1 upregulation occur via direct transcriptional activation mediated by β-catenin/TCF1. Thus, the balance between PGAM5-mediated dephosphorylation of ME1 S336 and ACAT1-mediated acetylation of K337 strongly influences NADPH generation, lipid metabolism, and the susceptibility to colorectal tumorigenesis.