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

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

Author information

1
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
3
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
4
Department of Genetics, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
5
Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
6
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
7
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York University, New York, NY 10016, USA.
8
Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
9
Department of Radiation System Biology, Institute of Radiation Biology Center, Kyoto University, Kyoto, Japan.
10
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
#
Contributed equally

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.

PMID:
27323329
PMCID:
PMC4936519
DOI:
10.1038/ncb3376
[Indexed for MEDLINE]
Free PMC Article

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