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

Author

Listed:
  • Sergey Karakashev

    (The Wistar Institute)

  • Hengrui Zhu

    (The Wistar Institute)

  • Shuai Wu

    (The Wistar Institute)

  • Yuhki Yokoyama

    (The Wistar Institute)

  • Benjamin G. Bitler

    (The Wistar Institute)

  • Pyoung-Hwa Park

    (The Wistar Institute)

  • Jeong-Heon Lee

    (Mayo Clinic)

  • Andrew V. Kossenkov

    (The Wistar Institute)

  • Krutika Satish Gaonkar

    (Mayo Clinic)

  • Huihuang Yan

    (Mayo Clinic)

  • Ronny Drapkin

    (University of Pennsylvania)

  • Jose R. Conejo-Garcia

    (Moffitt Cancer Center)

  • David W. Speicher

    (The Wistar Institute)

  • Tamas Ordog

    (Mayo Clinic)

  • Rugang Zhang

    (The Wistar Institute)

Abstract

CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 is often overexpressed in human cancers. However, clinically applicable cancer therapeutic strategies based on CARM1 expression remain to be explored. Here, we report that EZH2 inhibition is effective in CARM1-expressing epithelial ovarian cancer. Inhibition of EZH2 activity using a clinically applicable small molecule inhibitor significantly suppresses the growth of CARM1-expressing, but not CARM1-deficient, ovarian tumors in two xenograft models and improves the survival of mice bearing CARM1-expressing ovarian tumors. The observed selectivity correlates with reactivation of EZH2 target tumor suppressor genes in a CARM1-dependent manner. Mechanistically, CARM1 promotes EZH2-mediated silencing of EZH2/BAF155 target tumor suppressor genes by methylating BAF155, which leads to the displacement of BAF155 by EZH2. Together, these results indicate that pharmacological inhibition of EZH2 represents a novel therapeutic strategy for CARM1-expressing cancers.

Suggested Citation

  • Sergey Karakashev & Hengrui Zhu & Shuai Wu & Yuhki Yokoyama & Benjamin G. Bitler & Pyoung-Hwa Park & Jeong-Heon Lee & Andrew V. Kossenkov & Krutika Satish Gaonkar & Huihuang Yan & Ronny Drapkin & Jose, 2018. "CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03031-3
    DOI: 10.1038/s41467-018-03031-3
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    Cited by:

    1. Hidehiro Itonaga & Adnan K. Mookhtiar & Sarah M. Greenblatt & Fan Liu & Concepcion Martinez & Daniel Bilbao & Masai Rains & Pierre-Jacques Hamard & Jun Sun & Afoma C. Umeano & Stephanie Duffort & Chua, 2024. "Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Pengfei Lv & Xingzhuo Yang & Juan Du, 2024. "LKRSDH-dependent histone modifications of insulin-like peptide sites contribute to age-related circadian rhythm changes," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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