TY - JOUR
T1 - CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity
AU - Karakashev, Sergey
AU - Zhu, Hengrui
AU - Wu, Shuai
AU - Yokoyama, Yuhki
AU - Bitler, Benjamin G.
AU - Park, Pyoung Hwa
AU - Lee, Jeong Heon
AU - Kossenkov, Andrew V.
AU - Gaonkar, Krutika Satish
AU - Yan, Huihuang
AU - Drapkin, Ronny
AU - Conejo-Garcia, Jose R.
AU - Speicher, David W.
AU - Ordog, Tamas
AU - Zhang, Rugang
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85042019205&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-03031-3
DO - 10.1038/s41467-018-03031-3
M3 - Article
C2 - 29434212
AN - SCOPUS:85042019205
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 631
ER -