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CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity

Sergey Karakashev1, Hengrui Zhu1, Shuai Wu1

  • 1Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.

Nature Communications
|February 14, 2018
PubMed

Insights

Targeting EZH2 with small molecule inhibitors shows promise for treating epithelial ovarian cancer that expresses CARM1 (Co-Activator Associated Arginine Methyltransferase 1). This approach reactivates tumor suppressor genes, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Co-Activator Associated Arginine Methyltransferase 1 (CARM1) is an enzyme involved in protein methylation.
  • CARM1 is frequently overexpressed in various human cancers, including epithelial ovarian cancer.
  • Effective therapeutic strategies targeting CARM1-expressing cancers are needed.

Purpose of the Study:

  • To investigate the therapeutic potential of EZH2 inhibition in CARM1-expressing epithelial ovarian cancer.
  • To elucidate the mechanism by which CARM1 influences EZH2 activity and tumor suppressor gene expression.

Main Methods:

  • Utilized a clinically applicable small molecule inhibitor of EZH2.
  • Tested the efficacy of EZH2 inhibition in CARM1-expressing and CARM1-deficient ovarian cancer xenograft models in mice.
  • Analyzed the impact of CARM1 on EZH2-mediated gene silencing and BAF155 interactions.

Main Results:

  • EZH2 inhibition significantly suppressed tumor growth in CARM1-expressing ovarian tumors but not in CARM1-deficient tumors.
  • Inhibition of EZH2 improved survival rates in mice with CARM1-expressing ovarian tumors.
  • CARM1-dependent reactivation of EZH2 target tumor suppressor genes was observed.
  • CARM1 promotes EZH2-mediated gene silencing by methylating BAF155, facilitating BAF155 displacement by EZH2.

Conclusions:

  • Pharmacological inhibition of EZH2 is a viable therapeutic strategy for CARM1-expressing epithelial ovarian cancer.
  • The findings reveal a novel mechanism involving CARM1 and EZH2 in regulating tumor suppressor genes.
  • This study opens avenues for developing targeted therapies for cancers with specific CARM1 expression profiles.

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