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The speckle-type POZ protein (SPOP) inhibits breast cancer malignancy by destabilizing TWIST1

Chunli Wei1, Yun Liu2, Xiaoyan Liu1

  • 1Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China.

Cell Death Discovery
|September 17, 2022
PubMed

Insights

Speckle-type POZ protein (SPOP) targets TWIST1 for degradation, suppressing breast cancer metastasis. Lower SPOP and higher TWIST1 levels indicate poor prognosis, especially in triple-negative breast cancer (TNBC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Epithelial-mesenchymal transition (EMT) transcription factor TWIST1 is crucial for cancer metastasis.
  • The role of the tumor-suppressive E3 ligase speckle-type POZ protein (SPOP) in regulating TWIST1 in breast cancer is not understood.

Purpose of the Study:

  • To investigate the regulatory mechanism of SPOP on TWIST1 in breast cancer.
  • To determine the clinical significance of the SPOP-TWIST1 interaction in breast cancer prognosis.

Main Methods:

  • Co-immunoprecipitation assays to confirm physical interaction between SPOP and TWIST1.
  • Ubiquitination assays to assess SPOP-mediated TWIST1 ubiquitination and degradation.
  • In vitro cell migration and invasion assays.
  • In vivo metastasis assays in mouse models.
  • Correlation analysis of SPOP and TWIST1 expression with clinical data from breast cancer patients.

Main Results:

  • SPOP directly interacts with TWIST1, leading to its ubiquitination and destabilization.
  • SPOP promotes both K63- and K48-linked ubiquitination of TWIST1, primarily at lysine 73.
  • SPOP-mediated TWIST1 degradation suppresses breast cancer cell migration, invasion, and in vivo lung metastasis.
  • Silencing SPOP enhances EMT, promoting cancer cell aggressiveness.
  • Clinical data show an inverse correlation between SPOP and TWIST1 levels in invasive breast carcinomas.
  • Low SPOP and high TWIST1 expression correlate with poor prognosis in advanced breast cancer, particularly in metastatic triple-negative breast cancer (TNBC).

Conclusions:

  • SPOP functions as a negative regulator of TWIST1 stability and promotes its degradation via ubiquitination.
  • The SPOP-TWIST1 axis plays a significant role in suppressing breast cancer metastasis.
  • SPOP represents a potential prognostic biomarker and therapeutic target for advanced TNBC.

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