Mitochondrial Acetyl-CoA Synthetase 3 is Biosignature of Gastric Cancer Progression

Cancer Med. 2018 Apr;7(4):1240-1252. doi: 10.1002/cam4.1295. Epub 2018 Mar 1.

Abstract

Cholesterol affects cancer progression, and acetyl-CoA is the primary cholesterogenesis substrate. The previous work has defined cholesterol bioflux via lipoprotein/receptor route is the gastric cancer (GCa) prognosis biosignature. The prognosis importance of acetyl-CoA to cholesterogenesis (mevalonate pathway) in GCa is yet to be defined. Using Kaplan-Meier Plotter web-based gene survival analyzer and The Cancer Genome Atlas (TCGA)-database analyzed with DBdriver.v2 platform, we revealed acetyl-CoA production and the mevalonate pathway are associated with GCa prognosis. We found mitochondrial-derived acetyl-CoA contributing enzymes (acyl-coA synthetase super-family 3; ACSS3) is the GCa progression confounder. Interestingly, it is not HMGCR (the committee enzyme of mevalonate pathway), but lower mevalonate pathway enzymes (e.g., MVK, LSS, DHCR14A1, SC4MOL, HSD17B7, SC5D) promote GCa patients 5-years overall survival in a differential level. Advanced analyses found ACSS3 is prognosis biosignatures for multiple GCa disease conditions. This report uncovered a higher expression of ACSS3 in tumor comparing to normal parental lesions, which implicates a targeting value for GCa therapy. While knockdown ACSS3 could suppress growth and invasion of GCa cells, of which even more impactful under starvation condition. This is the first report, surprisingly, revealed ACSS3 as important cancer prognosis biomarker. Targeting ACSS3 could be a novel therapeutic strategy for cancer, in this case, GCa.

Keywords: Cholesterol; Gastric Cancer; Mevalonate pathway; acyl-coA synthetase superfamily 3.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetate-CoA Ligase / metabolism*
  • Apoptosis / genetics
  • Biomarkers
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cholesterol / metabolism
  • Databases, Genetic
  • Disease Progression
  • Energy Metabolism / drug effects
  • Humans
  • Metabolic Networks and Pathways / drug effects
  • Mevalonic Acid / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Models, Biological
  • Neoplasm Staging
  • Prognosis
  • Proportional Hazards Models
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology*
  • Stress, Physiological

Substances

  • Biomarkers
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • Cholesterol
  • Acetate-CoA Ligase
  • Mevalonic Acid