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OTUB1 inhibits breast cancer by non-canonically stabilizing CCN6

Ying Zhao1,2, Jing Ruan3, Zhongding Li1

  • 1Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.

Clinical and Translational Medicine
|August 23, 2023
PubMed
Abstract

Insights

OTUB1 deubiquitinates and stabilizes CCN6, a tumor suppressor in breast cancer. OTUB1 downregulation in breast cancer promotes tumor progression by reducing CCN6 levels.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • CCN6 is a critical matricellular protein regulating breast cancer tumorigenesis.
  • Mechanisms controlling CCN6 protein levels, particularly via ubiquitination, are not well understood.

Purpose of the Study:

  • To investigate the role of deubiquitinating enzymes (DUBs) in regulating CCN6 protein levels.
  • To elucidate the specific DUB responsible for CCN6 regulation and its mechanism in breast cancer.

Main Methods:

  • Screening assay to identify DUBs targeting CCN6.
  • Biochemical assays to define the OTUB1-CCN6 interaction and mechanism.
  • Cellular and in vivo models to assess the functional impact of OTUB1-CCN6 interaction.
  • Immunohistochemistry and Western blot to analyze OTUB1 and CCN6 expression in human breast cancer tissues.

Main Results:

  • OTUB1 was identified as a DUB that directly interacts with CCN6.
  • OTUB1 inhibits K48-linked ubiquitination and proteasomal degradation of CCN6 in a non-canonical manner.
  • OTUB1 downregulation in breast cancer leads to decreased CCN6 levels, enhancing cancer cell migration, proliferation, and viability.
  • OTUB1 expression inversely correlates with breast cancer progression.

Conclusions:

  • OTUB1 is a novel deubiquitinating enzyme that stabilizes the tumor suppressor CCN6 in breast cancer.
  • OTUB1 acts as a potential therapeutic target for breast cancer treatment by restoring CCN6 levels.
Keywords:
CCN6OTUB1breast cancerprotein degradationubiquitination

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