A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

Cancer Cell. 2017 Feb 13;31(2):208-224. doi: 10.1016/j.ccell.2017.01.003. Epub 2017 Feb 2.

Abstract

UBE2O is localized in the 17q25 locus, which is known to be amplified in human cancers, but its role in tumorigenesis remains undefined. Here we show that Ube2o deletion in MMTV-PyVT or TRAMP mice profoundly impairs tumor initiation, growth, and metastasis, while switching off the metabolic reprogramming of tumor cells. Mechanistically, UBE2O specifically targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Notably, inactivation of AMPKα2, but not AMPKα1, abrogates the tumor attenuation caused by UBE2O loss, while treatment with rapamycin or inhibition of HIF1α ablates UBE2O-dependent tumor biology. Finally, pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2, suggesting the UBE2O-AMPKα2 axis as a potential cancer therapeutic target.

Keywords: AMPK; AMPKα2; HIF1α; UBE2O; arsenite; breast cancer; cancer metabolism; mTOR; prostate cancer; ubiquitination.

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / physiology*
  • Animals
  • Antigens, Neoplasm / metabolism
  • Disease Progression
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / etiology*
  • TOR Serine-Threonine Kinases / physiology
  • Ubiquitin-Conjugating Enzymes / antagonists & inhibitors
  • Ubiquitin-Conjugating Enzymes / physiology*
  • Ubiquitination

Substances

  • Antigens, Neoplasm
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MAGEA3 protein, human
  • Neoplasm Proteins
  • Ubiquitin-Conjugating Enzymes
  • UBE2O protein, human
  • PRKAA2 protein, human
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases