PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia

Nat Cell Biol. 2016 Jul;18(7):803-813. doi: 10.1038/ncb3376. Epub 2016 Jun 20.

Abstract

Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor (HIF) controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-tyrosine phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, although the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2(+) xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2(+) BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The moyamoya disease gene product RNF213, an E3 ligase, is negatively regulated by PTP1B in HER2(+) BC cells. RNF213 knockdown reverses the effects of PTP1B deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2(+) BC cells, and partially restores tumorigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2(+) BC, and possibly other malignancies, in the hypoxic tumour microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
  • Animals
  • Breast Neoplasms / metabolism
  • Cell Hypoxia
  • Female
  • Genes, erbB-2 / genetics
  • Humans
  • Mice
  • Mitochondria / metabolism
  • Oxygen Consumption / physiology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • RNF213 protein, human
  • RNF213 protein, mouse
  • Ubiquitin-Protein Ligases
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse
  • Adenosine Triphosphatases