2. Academic Validation
  3. The deubiquitylating enzyme USP35 restricts regulated cell death to promote survival of renal clear cell carcinoma

The deubiquitylating enzyme USP35 restricts regulated cell death to promote survival of renal clear cell carcinoma

  • Cell Death Differ. 2023 May 12. doi: 10.1038/s41418-023-01176-3.
Shanshan Wang # 1,  Taishu Wang # 1 2,  Xuehong Zhang 1,  Shaoxuan Cheng 1,  Chaoqun Chen 1,  Guoheng Yang 1,  Fuqiang Wang 1,  Ruilin Wang 1,  Qingqing Zhang 3,  Dian Yang 1,  Yingqiu Zhang 1,  Shuyan Liu 1,  Hongqiang Qin 4,  Quentin Liu 1,  Han Liu 5
Affiliations

Affiliations

  • 1 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • 2 National Institute of Biological Sciences, Beijing, China.
  • 3 Department of Pathology, Dalian Medical University, Dalian, China.
  • 4 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
  • 5 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. liuhan@dmu.edu.cn.
  • # Contributed equally.
PMID: 37173391 DOI: 10.1038/s41418-023-01176-3
Abstract

The ubiquitin-proteasome system governs a wide spectrum of cellular events and offers therapeutic opportunities for pharmacological intervention in Cancer treatment. Renal clear cell carcinoma represents the predominant histological subtype and accounts for the majority of Cancer death related to kidney malignancies. Through a systematic survey in the association of human ubiquitin-specific proteases with patient prognosis of renal clear cell carcinoma and subsequent phenotypic validation, we uncovered the tumor-promoting role of USP35. Biochemical characterizations confirmed the stabilizing effects of USP35 towards multiple members of the IAP family in an enzymatic activity-dependent manner. USP35 silencing led to reduced expression levels of IAP proteins, which were accompanied with increased cellular Apoptosis. Further transcriptomic analysis revealed that USP35 knockdown affected the expression levels of NRF2 downstream transcripts, which were conferred by compromised NRF2 abundance. USP35 functions to maintain NRF2 levels by catalyzing its deubiquitylation and thus antagonizing degradation. NRF2 reduction imposed by USP35 silencing rendered renal clear cell carcinoma cells increased sensitivity to Ferroptosis induction. Finally, induced USP35 knockdown markedly attenuated xenograft formation of renal clear cell carcinoma in nude mice. Hence, our findings reveal a number of USP35 substrates and uncover the protecting roles of USP35 against both Apoptosis and Ferroptosis in renal clear cell carcinoma.

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