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13:05
De Novo Generation of Somatic Stem Cells by YAP/TAZ
Published on: May 7, 2018
9.6K
A feed forward loop enforces YAP/TAZ signaling during tumorigenesis
Mandeep K Gill1,2, Tania Christova1,2, Ying Y Zhang3,4
1Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Nature Communications
|August 31, 2018
Summary
Researchers discovered NUAK2 activates YAP/TAZ signaling, promoting cancer growth. Inhibiting NUAK2 slowed tumor growth in mice, suggesting NUAK2 as a potential cancer therapeutic target for reactivating the Hippo pathway.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- The Hippo pathway regulates organ size and is often inactivated in solid tumors.
- Yeast and TAZ (transcriptional co-activators) are key downstream effectors of the Hippo pathway.
- Mechanisms of Hippo pathway inactivation and YAP/TAZ activation in cancer are not fully understood.
Purpose of the Study:
- To identify novel regulators of YAP/TAZ activity in cancer.
- To investigate the role of NUAK2 in Hippo pathway signaling and tumor progression.
- To explore NUAK2 as a potential therapeutic target for YAP/TAZ-driven cancers.
Main Methods:
- Investigated NUAK2's interaction with YAP/TAZ and LATS kinase.
- Assessed the impact of NUAK2 inhibition on cancer cell growth and mammary tumor development in mouse models.
- Analyzed NUAK2 expression and its correlation with YAP/TAZ signatures in human bladder cancer patient samples.
Main Results:
- NUAK2 was identified as a direct activator of YAP/TAZ by inhibiting LATS-mediated phosphorylation.
- NUAK2 expression is induced by YAP/TAZ and AP-1, forming a positive feedback loop.
- Pharmacological inhibition or genetic loss of NUAK2 suppressed cancer cell proliferation and mammary tumor growth in vivo.
- Elevated NUAK2 expression in aggressive bladder cancer correlated strongly with YAP/TAZ gene signatures.
Conclusions:
- NUAK2 plays a critical role in sustaining YAP/TAZ signaling and promoting tumor growth.
- A positive feedback loop involving NUAK2, YAP/TAZ, and AP-1 reinforces oncogenic signaling.
- NUAK2 represents a promising therapeutic target for reactivating the Hippo pathway in YAP/TAZ-driven cancers.
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