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

Publication ,  Journal Article
Karakashev, S; Zhu, H; Wu, S; Yokoyama, Y; Bitler, BG; Park, P-H; Lee, J-H; Kossenkov, AV; Gaonkar, KS; Yan, H; Drapkin, R; Conejo-Garcia, JR ...
Published in: Nat Commun
February 12, 2018

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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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

February 12, 2018

Volume

9

Issue

1

Start / End Page

631

Location

England

Related Subject Headings

  • Transcription Factors
  • Protein-Arginine N-Methyltransferases
  • Ovarian Neoplasms
  • Neoplasms, Glandular and Epithelial
  • Mice
  • Humans
  • Female
  • Enhancer of Zeste Homolog 2 Protein
  • Cell Line, Tumor
  • Carcinoma, Ovarian Epithelial
 

Citation

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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. Nat Commun, 9(1), 631. https://doi.org/10.1038/s41467-018-03031-3
Karakashev, Sergey, Hengrui Zhu, Shuai Wu, Yuhki Yokoyama, Benjamin G. Bitler, Pyoung-Hwa Park, Jeong-Heon Lee, et al. “CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity.Nat Commun 9, no. 1 (February 12, 2018): 631. https://doi.org/10.1038/s41467-018-03031-3.
Karakashev S, Zhu H, Wu S, Yokoyama Y, Bitler BG, Park P-H, et al. CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun. 2018 Feb 12;9(1):631.
Karakashev, Sergey, et al. “CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity.Nat Commun, vol. 9, no. 1, Feb. 2018, p. 631. Pubmed, doi:10.1038/s41467-018-03031-3.
Karakashev S, Zhu H, Wu S, Yokoyama Y, Bitler BG, Park P-H, Lee J-H, Kossenkov AV, Gaonkar KS, Yan H, Drapkin R, Conejo-Garcia JR, Speicher DW, Ordog T, Zhang R. CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun. 2018 Feb 12;9(1):631.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

February 12, 2018

Volume

9

Issue

1

Start / End Page

631

Location

England

Related Subject Headings

  • Transcription Factors
  • Protein-Arginine N-Methyltransferases
  • Ovarian Neoplasms
  • Neoplasms, Glandular and Epithelial
  • Mice
  • Humans
  • Female
  • Enhancer of Zeste Homolog 2 Protein
  • Cell Line, Tumor
  • Carcinoma, Ovarian Epithelial