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Acquired platinum resistance involves epithelial to mesenchymal transition through ubiquitin ligase FBXO32

Nobuyuki Tanaka1, Takeo Kosaka1, Yasumasa Miyazaki1

  • 1Department of Urology, Keio University School of Medicine, Tokyo, Japan.

JCI Insight
|November 5, 2016
PubMed

Insights

The ubiquitin E3 ligase FBXO32 acts as a negative regulator of epithelial to mesenchymal transition (EMT) in urothelial carcinoma (UC) that has developed platinum resistance. FBXO32 dysregulation promotes EMT, impacting cancer progression and treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Acquired platinum resistance in urothelial carcinoma (UC) is a significant clinical challenge.
  • Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer progression and drug resistance.
  • Understanding the molecular mechanisms underlying EMT in platinum-resistant UC is essential for developing new therapeutic strategies.

Purpose of the Study:

  • To identify key molecules involved in EMT in UC following platinum treatment resistance.
  • To investigate the role of ubiquitin E3 ligase FBXO32 in regulating EMT in platinum-resistant UC.
  • To explore the therapeutic implications of FBXO32 in UC treatment.

Main Methods:

  • Global gene expression analysis using microarray in UC cell lines and their platinum-resistant sublines.
  • In vitro and in vivo studies to assess the relationship between FBXO32 expression and EMT markers.
  • Validation of findings using clinical UC samples.
  • Comparative genomic hybridization array analysis to identify genetic alterations.

Main Results:

  • FBXO32 was identified as a novel negative regulator of EMT in platinum-resistant UC.
  • FBXO32 dysregulation in resistant cells led to increased expression of mesenchymal markers (SNAIL, vimentin) and decreased epithelial marker (E-cadherin).
  • Knockdown of MyoD, an FBXO32 target, reversed EMT markers, confirming FBXO32's role.
  • Loss of heterozygosity at 8q24.13, harboring FBXO32, was observed in resistant cells.

Conclusions:

  • FBXO32 is a critical regulator of EMT in acquired platinum resistance in UC.
  • The ubiquitin-proteasome system, through FBXO32, is closely associated with EMT development in platinum-resistant tumors.
  • Targeting FBXO32 or related pathways may offer a novel therapeutic approach for platinum-resistant UC.

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