NUAK2 is a critical YAP target in liver cancer

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. Chromatin immunoprecipitation was done for primary hepatocytes of TetO-YAP S127A mice placed on Dox for four days. Chromatin immunoprecipitation was performed essentially as previously described in Galli et al Mol Cell. 2015 Oct 15;60(2):328-37. Chromatin immunoprecipitation was done for H3K27Ac histone mark, Yap and Tead4 proteins. Input DNA was used as reference for peak calling.