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Microtubule dynamics is a therapeutic vulnerability in VHL-deficient renal cell carcinoma

Yue Pu1, Ziruoyu Wang2, Shishi Tao1,3

  • 1Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.

International Journal of Biological Sciences
|May 19, 2025
PubMed

Insights

Von Hippel-Lindau (VHL) deficiency creates a vulnerability in renal cell carcinoma (RCC) that can be targeted. SKPin C1, a microtubule-disrupting agent, selectively kills VHL-deficient RCC cells by altering microtubule dynamics.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Von Hippel-Lindau (VHL) is a tumor suppressor gene frequently mutated in renal cell carcinoma (RCC).
  • Loss of VHL function is a potential therapeutic target in RCC.
  • Identifying synthetic lethal interactions in VHL-deficient RCC is crucial for developing novel treatments.

Purpose of the Study:

  • To identify therapeutic vulnerabilities in VHL-deficient RCC.
  • To investigate the mechanism of action of SKPin C1 in VHL-deficient RCC cells.
  • To explore the role of microtubule dynamics in VHL-deficient RCC.

Main Methods:

  • Screening of VHL-deficient RCC cells with SKPin C1, a SKP2 inhibitor.
  • Biochemical and molecular interaction studies to determine SKPin C1's binding targets.
  • Analysis of microtubule dynamics, spindle assembly, and cell death induction.
  • Assessment of GTP-tubulin and acetylated microtubule levels.

Main Results:

  • SKPin C1 exhibited synthetic lethal effects on VHL-deficient RCC cells, independent of SKP2 inhibition.
  • SKPin C1 selectively disrupted spindle assembly and induced mitotic arrest and death in VHL-deficient RCC.
  • SKPin C1 binds to tubulin and inhibits microtubule polymerization, with a more pronounced effect in VHL-deficient cells.
  • VHL loss alters microtubule dynamics, increasing growth speed and decreasing stability.
  • SKPin C1 and other microtubule destabilizers suppressed microtubule growth and reduced GTP-tubulin and acetylated microtubules in VHL-deficient RCC.

Conclusions:

  • Microtubule dynamics represent a therapeutic vulnerability in VHL-deficient RCC.
  • SKPin C1 selectively targets VHL-deficient RCC by disrupting microtubule dynamics.
  • Combination therapy of VHL-deficient RCC with anti-microtubule agents and targeted therapies is a promising strategy.
Keywords:
VHLdrug targetmicrotubulerenal cell carcinomasynthetic lethality

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