CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity [RNA-Seq]

CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 is often overexpressed in cancers and stimulates growth. However, clinically applicable therapeutic strategies based on CARM1 expression in cancer remains to be explored. Here we show that epithelial ovarian cancer is among the cancers with the highest CARM1 amplification rates that predicates a shorter survival. Our unbiased screen show that CARM1-expressing ovarian cancer cells are selectively sensitive to the inhibition of EZH2, another epigenetic regulator that silences its target genes. Inhibition of EZH2 activity using a clinically applicable small molecule inhibitor significantly suppressed the growth of CARM1-expressing ovarian tumors in two xenograft models. The observed selectivity correlates with upregulation of EZH2 target genes in a CARM1-dependent manner. CARM1 promotes EZH2 dependent gene silencing by methylating BAF155 to alter the antagonism between EZH2 and BAF155. Together, these results indicate that pharmacological inhibition of EZH2 is a novel therapeutic strategy for CARM1-expressing cancers. Overall design: CARM1 wild type and knockout samples assayed by RNA-seq

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Karakashev S, Zhu H, Wu S, Yokoyama Y, Bitler BG, Park PH, Lee JH, Kossenkov AV, Gaonkar KS, Yan H, Drapkin R, Conejo-Garcia JR, Speicher DW, Ordog T, Zhang R