title: GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment.
abstract: The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasisin vivoTaken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting.Cancer Res; 77(11); 2844-56. ©2017 AACR.
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Schnepp
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Guldner
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.
authors.forename: Treasa K
authors.initials: TK
authors.lastname: O'Tighearnaigh
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Howe
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Palakurthi
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.
authors.forename: Kaitlyn E
authors.initials: KE
authors.lastname: Eckert
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Toni
authors.affiliation: Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.|Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Ashfeld
authors.affiliation: Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana. szhang8@nd.edu.|Mike and Josie Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.|Indiana University Melvin & Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D019295:Computational Biology; D019175:DNA Methylation; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D014162:Transfection; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1