USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5

J Biol Chem. 2019 Nov 22;294(47):17837-17847. doi: 10.1074/jbc.RA119.009102. Epub 2019 Oct 17.

Abstract

The Krüppel-like factor 5 (KLF5) transcription factor is highly expressed in basal type breast cancer and promotes breast cancer cell proliferation, survival, migration, and tumorigenesis. KLF5 protein stability is regulated by ubiquitination. In this study, ubiquitin-specific protease 3 (USP3) was identified as a new KLF5 deubiquitinase by genome-wide siRNA library screening. We demonstrated that USP3 interacts with KLF5 and stabilizes KLF5 via deubiquitination. USP3 knockdown inhibits breast cancer cell proliferation in vitro and tumorigenesis in vivo, which can be partially rescued by ectopic expression of KLF5. Furthermore, we observed a positive correlation between USP3 and KLF5 protein expression levels in human breast cancer samples. These findings suggest that USP3 is a new KLF5 deubiquitinase and that USP3 may represent a potential therapeutic target for breast cancer.

Keywords: DUB; KLF5; USP3; breast cancer; cell growth; cell proliferation; ubiquitin; ubiquitin-dependent protease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • HEK293 Cells
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice, Nude
  • Protein Binding
  • Protein Stability
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Ubiquitin-Specific Proteases / metabolism*
  • Ubiquitination*

Substances

  • KLF5 protein, human
  • Kruppel-Like Transcription Factors
  • USP3 protein, human
  • Ubiquitin-Specific Proteases