BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells

J Cell Biol. 2017 Dec 4;216(12):4091-4105. doi: 10.1083/jcb.201701064. Epub 2017 Nov 7.

Abstract

Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • CRISPR-Associated Protein 9
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Cell Proliferation
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Endonucleases / genetics
  • Endonucleases / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Editing
  • Gene Expression Regulation, Neoplastic*
  • Glucose / metabolism
  • Glycolysis / genetics
  • Hexokinase / genetics*
  • Hexokinase / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Primary Cell Culture
  • RNA, Guide / genetics
  • RNA, Guide / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BAG3 protein, human
  • Bacterial Proteins
  • IGF2BP3 protein, human
  • RC3H1 protein, human
  • RNA, Guide
  • RNA, Messenger
  • RNA-Binding Proteins
  • Ubiquitin-Protein Ligases
  • HK2 protein, human
  • Hexokinase
  • CRISPR-Associated Protein 9
  • Cas9 protein, Francisella novicida
  • Endonucleases
  • Glucose