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The deubiquitinase USP10 regulates KLF4 stability and suppresses lung tumorigenesis

Xingyun Wang1,2, Shilin Xia3, Hongchang Li4

  • 1Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.

Cell Death and Differentiation
|November 22, 2019
PubMed

Insights

Ubiquitin-specific peptidase 10 (USP10) stabilizes Krüppel-like factor 4 (KLF4) protein levels, inhibiting lung cancer progression. Loss of USP10 accelerates tumor growth, highlighting the USP10-KLF4-TIMP3 pathway as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Krüppel-like factor 4 (KLF4) is crucial in aggressive cancer progression.
  • Protein stability, regulated by ubiquitination and deubiquitination, controls KLF4 levels.
  • Deubiquitinases targeting KLF4 remain largely uncharacterized.

Purpose of the Study:

  • To identify deubiquitinating enzymes that regulate KLF4.
  • To elucidate the role of USP10 in KLF4 stability and cancer.
  • To investigate the therapeutic potential of the USP10-KLF4-TIMP3 axis in lung cancer.

Main Methods:

  • Screening of ubiquitin-specific proteases for KLF4 interaction.
  • Functional assays involving USP10 overexpression and depletion.
  • In vivo studies using KrasG12D-driven lung adenocarcinoma mouse models.
  • Analysis of KLF4 binding to the TIMP3 promoter.
  • Clinical correlation analysis of USP10, KLF4, and TIMP3 expression in lung cancer patients.

Main Results:

  • Ubiquitin-specific peptidase 10 (USP10) was identified as a KLF4 deubiquitinase.
  • USP10 overexpression stabilizes KLF4, while USP10 depletion promotes KLF4 degradation and tumorigenesis.
  • Loss of USP10 accelerated KrasG12D-driven lung adenocarcinoma in mice.
  • KLF4 directly promotes transcription of the tumor suppressor TIMP3.
  • Reduced USP10, KLF4, and TIMP3 expression correlated with poor prognosis in lung cancer patients.

Conclusions:

  • USP10 is a critical regulator of KLF4 stability.
  • The USP10-KLF4-TIMP3 signaling axis plays a significant role in lung cancer.
  • Targeting the USP10-KLF4-TIMP3 pathway offers a promising therapeutic strategy for lung cancer.

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