PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia.
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.
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Robert S
RS
Banh
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Caterina
C
Iorio
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Richard
R
Marcotte
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Yang
Y
Xu
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Dan
D
Cojocari
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.|Department of Genetics, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Anas Abdel
AA
Rahman
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
Judy
J
Pawling
Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
Wei
W
Zhang
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Ankit
A
Sinha
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Christopher M
CM
Rose
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Marta
M
Isasa
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York University, New York, NY 10016, USA.
Shuang
S
Zhang
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Ronald
R
Wu
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Carl
C
Virtanen
Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Toshiaki
T
Hitomi
Department of Radiation System Biology, Institute of Radiation Biology Center, Kyoto University, Kyoto, Japan.
Toshiyuki
T
Habu
Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
Sachdev S
SS
Sidhu
Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Akio
A
Koizumi
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
Sarah E
SE
Wilkins
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Thomas
T
Kislinger
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Steven P
SP
Gygi
Chemistry Research Laboratory, Oxford University, 12 Mansfield Road, Oxford OX1 3TA, UK.
Christopher J
CJ
Schofield
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
James W
JW
Dennis
Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
Bradly G
BG
Wouters
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.|Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York University, New York, NY 10016, USA.
Benjamin G
BG
Neel
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D015687:Cell Hypoxia; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C557998:RNF213 protein, human; C583291:RNF213 protein, mouse; D044767:Ubiquitin-Protein Ligases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D000251:Adenosine Triphosphatases