ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma Academic Article uri icon


MeSH Major

  • Activating Transcription Factor 4
  • Cancer-Associated Fibroblasts
  • Glutamine
  • Prostatic Neoplasms
  • RNA-Binding Proteins
  • Stress, Physiological
  • Tumor Microenvironment


  • Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.

publication date

  • December 5, 2017



  • Academic Article



  • eng

PubMed Central ID

  • PMC5718961

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2017.09.001

PubMed ID

  • 28988820

Additional Document Info

start page

  • 817

end page

  • 829.e6


  • 26


  • 6