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

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 R. Conejo-Garcia, David W. Speicher, Tamas Ordog and Rugang Zhang ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03031-3

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