2. Academic Validation
  3. NUAK2 is a critical YAP target in liver cancer

NUAK2 is a critical YAP target in liver cancer

  • Nat Commun. 2018 Nov 16;9(1):4834. doi: 10.1038/s41467-018-07394-5.
Wei-Chien Yuan 1 2 3,  Brian Pepe-Mooney 1 2,  Giorgio G Galli 1 2 3 4,  Michael T Dill 1 2 3,  Hai-Tsang Huang 5 6,  Mingfeng Hao 6,  Yumeng Wang 7,  Han Liang 7,  Raffaele A Calogero 8,  Fernando D Camargo 9 10 11
Affiliations

Affiliations

  • 1 Stem Cell Program, Boston Children's Hospital, Boston, MA, 02115, USA.
  • 2 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
  • 3 Harvard Stem Cell Institute, Boston, MA, 02115, USA.
  • 4 Novartis Institutes for BioMedical Research, Disease Area Oncology, 4057, Basel, Switzerland.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
  • 7 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 8 Department of Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, 10126, Italy.
  • 9 Stem Cell Program, Boston Children's Hospital, Boston, MA, 02115, USA. [email protected].
  • 10 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. [email protected].
  • 11 Harvard Stem Cell Institute, Boston, MA, 02115, USA. [email protected].
PMID: 30446657 DOI: 10.1038/s41467-018-07394-5
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.

Figures
Products