NUAK2 is a critical YAP target in liver cancer

Wei-Chien Yuan, Brian Pepe-Mooney, Giorgio G. Galli, Michael T. Dill, Hai-Tsang Huang, Mingfeng Hao, Yumeng Wang, Han Liang, Raffaele A. Calogero and Fernando D. Camargo ()
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Wei-Chien Yuan: Boston Children’s Hospital
Brian Pepe-Mooney: Boston Children’s Hospital
Giorgio G. Galli: Boston Children’s Hospital
Michael T. Dill: Boston Children’s Hospital
Hai-Tsang Huang: Dana-Farber Cancer Institute
Mingfeng Hao: Harvard Medical School
Yumeng Wang: The University of Texas MD Anderson Cancer Center
Han Liang: The University of Texas MD Anderson Cancer Center
Raffaele A. Calogero: University of Torino
Fernando D. Camargo: Boston Children’s Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract The Hippo-YAP signaling pathway is a critical regulator of proliferation, apoptosis, and cell fate. The main downstream effector of this pathway, YAP, has been shown to be misregulated in human cancer and has emerged as an attractive target for therapeutics. A significant insufficiency in our understanding of the pathway is the identity of transcriptional targets of YAP that drive its potent growth phenotypes. Here, using liver cancer as a model, we identify NUAK2 as an essential mediator of YAP-driven hepatomegaly and tumorigenesis in vivo. By evaluating several human cancer cell lines we determine that NUAK2 is selectively required for YAP-driven growth. Mechanistically, we found that NUAK2 participates in a feedback loop to maximize YAP activity via promotion of actin polymerization and myosin activity. Additionally, pharmacological inactivation of NUAK2 suppresses YAP-dependent cancer cell proliferation and liver overgrowth. Importantly, our work here identifies a specific, potent, and actionable target for YAP-driven malignancies.

Date: 2018
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DOI: 10.1038/s41467-018-07394-5

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