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OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity

Fangzhou Li1, Qianqian Sun1, Kun Liu1

  • 1Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, China.

Nature Communications
|August 23, 2020
PubMed

Insights

The ovarian tumor domain-containing protein 5 (OTUD5) suppresses cancer growth by regulating TRIM25 ubiquitination. Reduced OTUD5 levels correlate with aggressive tumors and poor patient outcomes, suggesting OTUD5 as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Oncogenic processes often target cell proliferation regulators, making their study crucial for improving cancer therapies.
  • The ovarian tumor (OTU) subfamily of deubiquitinases is involved in cell signaling, but the functions of most OTUs remain unclear.
  • Investigating novel regulators of cell proliferation is essential for advancing oncotherapy.

Purpose of the Study:

  • To investigate the role of OTUD5 (ovarian tumor domain-containing protein 5) in regulating cell proliferation and tumorigenesis.
  • To elucidate the molecular mechanism by which OTUD5 influences gene expression and cancer progression.
  • To assess the clinical significance of OTUD5 expression in human cancers.

Main Methods:

  • Unbiased RNA interference (RNAi) screen to identify genes regulating cell growth.
  • Analysis of TRIM25 ubiquitination levels and its impact on transcriptional activity.
  • In vivo studies using a nude mouse model to evaluate tumor growth.
  • Correlation analysis of OTUD5 expression with tumor phenotype and clinical outcomes in cancer patients.

Main Results:

  • OTUD5 knockdown significantly accelerated cell growth in vitro.
  • OTUD5 depletion enhanced the transcriptional activity of TRIM25 and inhibited PML expression by altering TRIM25 ubiquitination.
  • OTUD5 knockdown accelerated tumor growth in a nude mouse model.
  • OTUD5 expression was markedly downregulated in tumor tissues and associated with aggressive phenotypes and poor clinical outcomes.

Conclusions:

  • OTUD5 suppresses tumorigenesis by deubiquitinating TRIM25, thereby regulating gene transcription.
  • Reduced OTUD5 levels are linked to cancer progression and poor prognosis.
  • OTUD5 represents a potential therapeutic target for oncotherapy.

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