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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

Published on: September 13, 2018

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A comprehensive evaluation of Hippo pathway silencing in sarcomas

Nicole M Merritt1, Colleen A Fullenkamp1, Sarah L Hall1

  • 1Department of Pathology, University of Iowa, Iowa City, IA, USA.

Oncotarget
|September 1, 2018
PubMed

Insights

Loss of Hippo kinases (MST1/2, LATS1/2) is frequent in sarcomas, activating oncoproteins TAZ/YAP. Mechanisms include post-translational degradation and epigenetic silencing via hypermethylation and histone deacetylation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • TAZ and YAP are key oncoproteins in various cancers, including sarcomas.
  • The Hippo pathway negatively regulates TAZ and YAP activity.
  • Loss of Hippo kinase expression is a potential mechanism for TAZ/YAP activation.

Purpose of the Study:

  • To investigate the frequency and mechanisms of Hippo kinase (MST1, MST2, LATS1, LATS2) loss of expression in sarcomas.
  • To determine if TAZ/YAP activation in clinical sarcoma samples correlates with Hippo kinase expression levels.

Main Methods:

  • Immunohistochemistry on clinical sarcoma samples.
  • Western blot analysis of sarcoma cell lines.
  • Quantitative reverse transcription PCR (qRT-PCR) to assess gene expression.
  • Treatment with MG132 (proteasome inhibitor), 5-azacytidine (demethylating agent), and Trichostatin A (histone deacetylase inhibitor).

Main Results:

  • Loss of Hippo kinases was observed in TAZ/YAP-activated clinical sarcoma samples (MST1: 47%, MST2: 26%, LATS1: 19%, LATS2: 27%).
  • Western blot confirmed loss of MST1 (58%), MST2 (25%), and LATS2 (17%).
  • MG132 treatment caused MST2 accumulation, indicating proteasomal degradation.
  • qRT-PCR showed reduced expression of MST1 (42%) and MST2 (25%) at the RNA level.
  • 5-azacytidine and Trichostatin A treatments partially restored MST1/MST2 expression, suggesting epigenetic silencing (CpG hypermethylation and histone deacetylation).

Conclusions:

  • Loss of Hippo kinase expression is a frequent event in sarcomas.
  • This loss contributes to TAZ/YAP activation, promoting oncogenesis.
  • Multiple mechanisms, including post-translational regulation and epigenetic silencing, underlie Hippo kinase loss in sarcomas.
Keywords:
Hippo pathwayTAZYAPepigeneticssarcoma

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