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USP15-mediated deubiquitination of FIS1 impairs mitochondrial function and sensitizes bladder cancer cells to

Ruxin Xiong1,2, Mingxu Wang1,2, Jiaming Du3

  • 1Science and Technology Research Center, Harbin Medical University Cancer Hospital, Harbin, 150080, China.

Oncogene
|July 27, 2026
PubMed

Insights

USP15 enhances bladder cancer radiosensitivity by regulating mitochondrial function. Targeting USP15-mediated oxidative phosphorylation (OXPHOS) with metformin offers a promising strategy to improve radiotherapy efficacy in bladder cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Radiation therapy is crucial for advanced invasive bladder cancer but often requires enhancement.
  • Identifying molecular targets that modulate radiosensitivity is essential for improving treatment outcomes.

Purpose of the Study:

  • To identify novel regulators of radiosensitivity in bladder cancer.
  • To investigate the role of USP15 in bladder cancer radiosensitivity and mitochondrial function.

Main Methods:

  • Investigated USP15's role in bladder cancer cells and orthotopic mouse models.
  • Utilized biochemical assays to elucidate the interaction between USP15, FIS1, and mitochondrial oxidative phosphorylation (OXPHOS).
  • Assessed the efficacy of metformin as a mitochondrial inhibitor in patient-derived xenograft (PDX) models.

Main Results:

  • USP15 was identified as a novel regulator of mitochondrial function and radiosensitivity in bladder cancer.
  • USP15 stabilizes FIS1 protein, leading to mitochondrial dysfunction and increased radiosensitivity.
  • USP15 overexpression combined with radiotherapy suppressed tumor growth in mouse models.
  • Metformin reversed radioresistance in low USP15-expressing bladder cancer, inhibiting tumor growth and improving survival in PDX models.

Conclusions:

  • USP15 plays a critical role in regulating bladder cancer radiosensitivity through mitochondrial OXPHOS.
  • Targeting USP15-mediated mitochondrial OXPHOS presents a potential therapeutic strategy to enhance radiotherapy efficacy.
  • This study provides a novel treatment approach for bladder cancer patients receiving radiotherapy.

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