CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity
| Autor: | Tamas Ordog, Krutika S. Gaonkar, David W. Speicher, Ronny Drapkin, Shuai Wu, Pyoung Hwa Park, Jeong Heon Lee, Benjamin G. Bitler, Sergey Karakashev, Huihuang Yan, Yuhki Yokoyama, Jose R. Conejo-Garcia, Andrew V. Kossenkov, Rugang Zhang, Hengrui Zhu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Protein-Arginine N-Methyltransferases CARM1 Arginine Science General Physics and Astronomy macromolecular substances Carcinoma Ovarian Epithelial Article General Biochemistry Genetics and Molecular Biology law.invention Mice 03 medical and health sciences law Cell Line Tumor medicine Animals Humans Gene silencing Enhancer of Zeste Homolog 2 Protein Neoplasms Glandular and Epithelial lcsh:Science Ovarian Neoplasms Multidisciplinary Chemistry EZH2 Cancer General Chemistry medicine.disease 3. Good health 030104 developmental biology Histone methyltransferase Cancer research Suppressor Female lcsh:Q Ovarian cancer Transcription Factors |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. CARM1 is an arginine methyltransferase often overexpressed in human cancer. Here, the authors show that EZH2 inhibition suppresses growth in CARM1-expressing epithelial ovarian cancer, and examine the mechanism of how CARM1 promotes EZH2-mediated tumor suppressor gene silencing. |
| Databáze: | OpenAIRE |
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