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JOSD2 promotes breast cancer metastasis by deubiquitinating and stabilizing SMAD4

Jiamin Du1, Jiao Wang1, Fujing Ge1

  • 1Institute of Pharmacology & Toxicology Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

Biochemical Pharmacology
|January 10, 2025
PubMed

Insights

The deubiquitinase josephin domain containing 2 (JOSD2) promotes breast cancer metastasis by stabilizing SMAD4. Inhibiting JOSD2 offers a potential therapeutic strategy for metastatic breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Breast cancer metastasis significantly impacts patient prognosis.
  • Molecular mechanisms driving metastasis require further elucidation.
  • Deubiquitinases play crucial roles in cellular processes, including cancer progression.

Purpose of the Study:

  • To investigate the role of josephin domain containing 2 (JOSD2) in breast cancer metastasis.
  • To identify molecular pathways associated with JOSD2 expression in breast cancer.
  • To evaluate JOSD2 as a potential therapeutic target for metastatic breast cancer.

Main Methods:

  • Database analysis (GEO, KEGG) to identify JOSD2 amplification and pathway enrichment.
  • In vitro and in vivo experiments to assess the effect of JOSD2 inhibition on metastasis.
  • Molecular studies to elucidate JOSD2's interaction with SMAD4.

Main Results:

  • JOSD2 is abnormally amplified in metastatic breast cancer and negatively correlates with prognosis.
  • Increased JOSD2 expression is linked to activation of the transforming growth factor beta (TGF-β) signaling pathway.
  • JOSD2 stabilizes SMAD4 by removing polyubiquitin chains, promoting metastasis.
  • RNA interference-mediated inhibition of JOSD2 suppressed breast cancer cell metastasis in vitro and in vivo.

Conclusions:

  • JOSD2 promotes breast cancer metastasis through stabilization of SMAD4 and activation of TGF-β signaling.
  • JOSD2 represents a novel therapeutic target for metastatic breast cancer.
  • Deubiquitinase inhibitors targeting JOSD2 hold promise for future breast cancer treatment, pending further research.
Keywords:
Breast cancerDeubiquitinaseJOSD2MetastasisSMAD4

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