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Nat Commun. 2018 Aug 29;9(1):3510. doi: 10.1038/s41467-018-05939-2.

A feed forward loop enforces YAP/TAZ signaling during tumorigenesis.

Author information

1
Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada.
2
Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.
3
Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
4
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
5
Department of Pathology, McGill University and Research Institute of the McGill University Health Center, Montreal, H4A 3J1, QC, Canada.
6
Department of Biomedical Sciences, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, 999077, Hong Kong, China.
7
City University of Hong Kong Shenzhen Research Institute, Shenzhen, Guangdong, 518057, China.
8
Program in Cell Biology, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
9
SPARC BioCentre, Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
10
Department of Surgery, Division of Urology, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, M5G 1X5, ON, Canada.
11
Department of Pathology, Toronto General Hospital, University Health Network, Toronto, ON, M5G 2C4, Canada.
12
Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada. liliana.attisano@utoronto.ca.
13
Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada. liliana.attisano@utoronto.ca.

Abstract

In most solid tumors, the Hippo pathway is inactivated through poorly understood mechanisms that result in the activation of the transcriptional regulators, YAP and TAZ. Here, we identify NUAK2 as a YAP/TAZ activator that directly inhibits LATS-mediated phosphorylation of YAP/TAZ and show that NUAK2 induction by YAP/TAZ and AP-1 is required for robust YAP/TAZ signaling. Pharmacological inhibition or loss of NUAK2 reduces the growth of cultured cancer cells and mammary tumors in mice. Moreover, in human patient samples, we show that NUAK2 expression is elevated in aggressive, high-grade bladder cancer and strongly correlates with a YAP/TAZ gene signature. These findings identify a positive feed forward loop in the Hippo pathway that establishes a key role for NUAK2 in enforcing the tumor-promoting activities of YAP/TAZ. Our results thus introduce a new opportunity for cancer therapeutics by delineating NUAK2 as a potential target for re-engaging the Hippo pathway.

PMID:
30158528
PMCID:
PMC6115388
DOI:
10.1038/s41467-018-05939-2
[Indexed for MEDLINE]
Free PMC Article

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