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ATXN3 promotes breast cancer metastasis by deubiquitinating KLF4

Haojing Zou1, Hongyan Chen2, Zhuan Zhou3

  • 1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.

Cancer Letters
|September 30, 2019
PubMed

Insights

Researchers discovered ATXN3 deubiquitinates Krüppel-like factor 4 (KLF4), stabilizing it and promoting breast cancer metastasis. High ATXN3/KLF4 levels predict poor prognosis, suggesting ATXN3 as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Krüppel-like factor 4 (KLF4) is a key transcription factor involved in cellular processes, with aberrant expression linked to cancer.
  • Posttranslational modifications (PTMs) regulate KLF4 stability, but its deubiquitination mechanism is poorly understood.
  • While E3 ligases targeting KLF4 are known, the enzymes responsible for its deubiquitination remain largely unidentified.

Purpose of the Study:

  • To identify deubiquitinating enzymes that regulate KLF4.
  • To investigate the role of ATXN3 in KLF4 stability and breast cancer progression.
  • To explore the clinical significance of ATXN3 and KLF4 expression in breast cancer patients.

Main Methods:

  • Screening of 65 deubiquitinating enzymes to identify KLF4 interactors.
  • Immunoprecipitation assays to confirm ATXN3-KLF4 binding and deubiquitination.
  • In vitro and in vivo assays to assess the role of ATXN3 in breast cancer cell metastasis.
  • Analysis of ATXN3 and KLF4 protein expression in human breast cancer specimens.

Main Results:

  • ATXN3 was identified as a deubiquitinating enzyme for KLF4.
  • ATXN3 directly binds to KLF4, leading to its deubiquitination and increased protein stability.
  • ATXN3 promotes breast cancer cell metastasis through KLF4.
  • Elevated ATXN3 and KLF4 expression correlates with poor prognosis in breast cancer patients.

Conclusions:

  • ATXN3 is a novel deubiquitinating enzyme of KLF4.
  • The ATXN3-KLF4 axis plays a significant role in breast cancer metastasis.
  • ATXN3 represents a potential therapeutic target for treating breast cancer metastasis.
Keywords:
ATXN3Breast cancerDeubiquitinating enzymeKLF4Metastasis

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