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 D Yan, Ronny Drapkin, Jose R. Conejo-Garcia, David W. Speicher, Tamas Ordog, Rugang Zhang

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article number631
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Ovarian Neoplasms
tumor suppressor genes
cancer
tumors
Tumors
inhibitors
mice
Neoplasms
Tumor Suppressor Genes
selectivity
proteins
Bearings (structural)
Genes
histone methyltransferase
coactivator-associated arginine methyltransferase 1
molecules
Heterografts
Arginine
Pharmacology
Molecules

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Karakashev, S., Zhu, H., Wu, S., Yokoyama, Y., Bitler, B. G., Park, P. H., ... Zhang, R. (2018). CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nature Communications, 9(1), [631]. https://doi.org/10.1038/s41467-018-03031-3

CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. / Karakashev, Sergey; Zhu, Hengrui; Wu, Shuai; Yokoyama, Yuhki; Bitler, Benjamin G.; Park, Pyoung Hwa; Lee, Jeong Heon; Kossenkov, Andrew V.; Gaonkar, Krutika Satish; Yan, Huihuang D; Drapkin, Ronny; Conejo-Garcia, Jose R.; Speicher, David W.; Ordog, Tamas; Zhang, Rugang.

In: Nature Communications, Vol. 9, No. 1, 631, 01.12.2018.

Research output: Contribution to journalArticle

Karakashev, S, Zhu, H, Wu, S, Yokoyama, Y, Bitler, BG, Park, PH, Lee, JH, Kossenkov, AV, Gaonkar, KS, Yan, HD, Drapkin, R, Conejo-Garcia, JR, Speicher, DW, Ordog, T & Zhang, R 2018, 'CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity', Nature Communications, vol. 9, no. 1, 631. https://doi.org/10.1038/s41467-018-03031-3
Karakashev, Sergey ; Zhu, Hengrui ; Wu, Shuai ; Yokoyama, Yuhki ; Bitler, Benjamin G. ; Park, Pyoung Hwa ; Lee, Jeong Heon ; Kossenkov, Andrew V. ; Gaonkar, Krutika Satish ; Yan, Huihuang D ; Drapkin, Ronny ; Conejo-Garcia, Jose R. ; Speicher, David W. ; Ordog, Tamas ; Zhang, Rugang. / CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.",
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