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ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer

Peijing Zhang1, Zhenna Xiao2, Shouyu Wang3

  • 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.

Cell Reports
|April 19, 2018
PubMed

Insights

Researchers discovered ZRANB1 as a deubiquitinase that stabilizes EZH2. Targeting ZRANB1 shows therapeutic potential against triple-negative breast cancer by destabilizing EZH2 and inhibiting tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Enhancer of Zeste Homolog 2 (EZH2) inhibitors show efficacy in specific cancers but not all.
  • EZH2 can drive cancer independently of its histone methyltransferase activity, suggesting alternative regulatory mechanisms.

Purpose of the Study:

  • To identify the deubiquitinase responsible for EZH2 stabilization.
  • To investigate the therapeutic potential of targeting this deubiquitinase in cancer, particularly triple-negative breast cancer (TNBC).

Main Methods:

  • Identification of ZRANB1 as the EZH2 deubiquitinase.
  • Assessment of ZRANB1 depletion effects on EZH2 stability and breast cancer cell growth.
  • Evaluation of ZRANB1 small interfering RNA (siRNA) and small-molecule inhibitor efficacy in preclinical TNBC models.
  • Correlation analysis of ZRANB1 and EZH2 levels with patient survival in breast cancer.

Main Results:

  • ZRANB1 was identified as the deubiquitinase that binds, deubiquitinates, and stabilizes EZH2.
  • Depletion of ZRANB1 led to EZH2 destabilization and inhibited breast cancer cell growth.
  • Systemic delivery of ZRANB1 siRNA demonstrated significant antitumor and antimetastatic effects in TNBC models.
  • A ZRANB1 inhibitor destabilized EZH2 and reduced TNBC cell viability.
  • Elevated ZRANB1 levels in breast cancer patients correlated with higher EZH2 levels and poorer survival.

Conclusions:

  • ZRANB1 is a key regulator of EZH2 stability.
  • Targeting ZRANB1 represents a promising therapeutic strategy for TNBC and potentially other cancers driven by EZH2.
  • The ZRANB1-EZH2 axis offers a novel target for cancer therapy.
Keywords:
EZH2ZRANB1breast cancerdeubiquitinase

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