PTP1B regulates non-mitochondrial oxygen consumption via RNF213 to promote tumour survival during hypoxia
Banh, Robert S.
Rahman, Anas Abdel
Rose, Christopher M.
Sidhu, Sachdev S.
Wilkins, Sarah E.
Schofield, Christopher J.
Dennis, James W.
Wouters, Bradly G.
Neel, Benjamin G.Note: Order does not necessarily reflect citation order of authors.
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CitationBanh, R. S., C. Iorio, R. Marcotte, Y. Xu, D. Cojocari, A. A. Rahman, J. Pawling, et al. 2016. “PTP1B regulates non-mitochondrial oxygen consumption via RNF213 to promote tumour survival during hypoxia.” Nature cell biology 18 (7): 803-813. doi:10.1038/ncb3376. http://dx.doi.org/10.1038/ncb3376.
AbstractTumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor 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, though 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 tumourigenicity. 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.
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