The deubiquitinating enzyme UCHL3 promotes anaplastic thyroid cancer progression and metastasis through Hippo

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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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Jianing Tang1,2,3, Qian Yang3, Chao Mao4,5

  • 1Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China.

Cell Death and Differentiation
|February 22, 2023
PubMed

Insights

Ubiquitin carboxyl terminal hydrolase L3 (UCHL3) stabilizes Yes-associated protein (YAP) in Anaplastic thyroid carcinoma (ATC). Inhibiting UCHL3 reduces ATC progression and increases chemotherapy sensitivity, suggesting UCHL3 as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The Hippo pathway effector Yes-associated protein (YAP) is crucial in cancer, but its regulation in Anaplastic thyroid carcinoma (ATC) is unclear.
  • Understanding YAP regulation is vital for developing targeted therapies for aggressive thyroid cancers.

Purpose of the Study:

  • To identify the deubiquitylase responsible for YAP stabilization in ATC.
  • To investigate the role of this deubiquitylase in ATC progression and its potential as a therapeutic target.

Main Methods:

  • Identified UCHL3 as a YAP deubiquitylase in ATC.
  • Assessed the impact of UCHL3 depletion on ATC progression, stemness, metastasis, and chemotherapy sensitivity.
  • Analyzed YAP protein levels and YAP/TEAD target gene expression following UCHL3 depletion.
  • Investigated the transcriptional regulation of UCHL3 by TEAD4.

Main Results:

  • UCHL3 deubiquitylates and stabilizes YAP in an activity-dependent manner.
  • UCHL3 depletion significantly inhibited ATC progression, reduced stem-like properties and metastasis, and enhanced chemotherapy sensitivity.
  • UCHL3 depletion decreased YAP protein levels and YAP/TEAD target gene expression.
  • TEAD4 transcriptionally activated UCHL3 expression by binding to its promoter.

Conclusions:

  • UCHL3 plays a critical role in stabilizing YAP, promoting tumorigenesis in ATC.
  • UCHL3 represents a promising therapeutic target for Anaplastic thyroid carcinoma treatment.

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