Ataxin-3 like (ATXN3L), a member of the Josephin family of deubiquitinating enzymes, promotes breast cancer proliferation by deubiquitinating Krüppel-like factor 5 (KLF5)

Oncotarget. 2015 Aug 28;6(25):21369-78. doi: 10.18632/oncotarget.4128.

Abstract

The Krüppel-like factor 5 (KLF5) has been suggested to promote breast cell proliferation, survival and tumorigenesis. KLF5 protein degradation is increased by several E3 ubiquitin ligases, including WWP1 and SCFFbw7, through the ubiquitin-proteasome pathway. However, the deubiquitinase (DUB) of KLF5 has not been demonstrated. In this study, we identified ATXN3L as a KLF5 DUB by genome-wide siRNA screening. ATXN3L directly binds to KLF5, decreasing its ubiquitination and thus degradation. Functionally, knockdown of ATXN3L inhibits breast cancer cell proliferation partially through KLF5. These findings reveal a previously unrecognized role of ATXN3L in the regulation of KLF5 stability in breast cancer. ATXN3L might be a therapeutic target for breast cancer.

Keywords: ATXN3L; DUB; KLF5; breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Endopeptidases / genetics*
  • Endopeptidases / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Library
  • HEK293 Cells
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Plasmids / metabolism
  • Protein Interaction Mapping
  • RNA, Small Interfering / metabolism
  • Ubiquitin-Specific Proteases / metabolism
  • Ubiquitination*

Substances

  • KLF5 protein, human
  • Kruppel-Like Transcription Factors
  • RNA, Small Interfering
  • Endopeptidases
  • ATXN3L protein, human
  • Ubiquitin-Specific Proteases