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NUAK2 is a critical YAP target in liver cancer

Wei-Chien Yuan1,2,3, Brian Pepe-Mooney1,2, Giorgio G Galli1,2,3,4

  • 1Stem Cell Program, Boston Children's Hospital, Boston, MA, 02115, USA.

Nature Communications
|November 18, 2018
PubMed

Insights

Researchers identified NUAK2 as a key driver of YAP-driven liver cancer growth. Targeting NUAK2 shows promise for treating YAP-dependent cancers by suppressing tumor proliferation and overgrowth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The Hippo-YAP signaling pathway regulates cell growth and is often dysregulated in human cancers.
  • YAP, a key effector, is a potential therapeutic target, but its growth-promoting targets are not fully understood.

Purpose of the Study:

  • To identify YAP transcriptional targets driving cancer growth, using liver cancer as a model.
  • To investigate the role of NUAK2 in YAP-mediated hepatomegaly and tumorigenesis.

Main Methods:

  • Liver cancer models were used to identify NUAK2 as a YAP target.
  • Human cancer cell lines were evaluated for NUAK2 dependency on YAP-driven growth.
  • Mechanistic studies explored the feedback loop between NUAK2 and YAP activity.

Main Results:

  • NUAK2 was identified as an essential mediator of YAP-driven liver cancer growth and tumorigenesis in vivo.
  • NUAK2 is selectively required for YAP-driven growth across various human cancer cell lines.
  • NUAK2 enhances YAP activity through a feedback loop involving actin polymerization and myosin activity.

Conclusions:

  • NUAK2 is a critical mediator of YAP-driven cancer proliferation and liver overgrowth.
  • Pharmacological inhibition of NUAK2 effectively suppresses YAP-dependent cancer cell proliferation.
  • NUAK2 represents a specific, actionable therapeutic target for YAP-driven malignancies.

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