Journal Article

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

Hitomi, Toshiaki, Habu, Toshiyuki, Cojocari, Dan, Rose, Christopher M., Pawling, Judy, Wu, Ronald, Xu, Yang, Isasa, Marta, Sidhu, Sachdev S., Banh, Robert S., Rahman, Anas Abdel, Koizumi, Akio, Virtanen, Carl, Zhang, Wei, Sinha, Ankit, Wouters, Bradly G., Marcotte, Richard, Gygi, Steven P., Neel, Benjamin G., Zhang, Shuang, Wilkins, Sarah E., Kislinger, Thomas, Iorio, Caterina, Dennis, James W., Schofield, Christopher J.

2016

Overview

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. Banh et al. show that PTP1B decreases non-mitochondrial oxygen consumption by regulating the RNF213/α-KGDD pathway, thus promoting hypoxic survival of cancer cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67 / 631/67/2327 / 631/67/327 / 64/60 / 82/51 / 82/58 / 96/106 / 96/95 / Adenosine Triphosphatases - metabolism / Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism / Animals / Biology / Breast cancer / Breast Neoplasms - metabolism / Cancer Research / Cell Biology / Cell Hypoxia / Developmental Biology / Energy consumption / Female / Genes, erbB-2 - genetics / Humans / Hypoxia / Kinases / Life Sciences / Mice / Mitochondria - metabolism / Oxygen / Oxygen consumption / Oxygen Consumption - physiology / Phosphatase / Physiological aspects / Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism / Proteins / Radiation / Stem Cells / Tumors / Ubiquitin-Protein Ligases - metabolism