利巴韦林通过下调PRMT5及组蛋白甲基化抑制结直肠癌生长

Abstract

Eukaryotic translation initiation factor 4E (eIF4E) and protein arginine methyltransferase 5 (PRMT5) are frequently overexpressed in colorectal cancer (CRC) tissues and associated with poor prognosis. Ribavirin , the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C therapy. The potential of ribavirin to treat CRC remains largely unknown. Ribavirin treatment in CRC cell lines drastically inhibited cell proliferation and colony formation, induced S phase arrest and reduced cyclin D1 , cyclin A/E and proliferating cell nuclear antigen (PCNA) levels in vitro, and suppressed tumorigenesis in mouse model of colitis-associated CRC. Mechanistically, ribavirin treatment significantly reduced PRMT5 and eIF4E protein levels and the accumulation of symmetric dimethylation of histone 3 at arginine 8 (H3R8me2s) and that of histone 4 at arginine 3 (H4R3me2s). Importantly, inhibition of PRMT5 by ribavirin resulted in promoted H3R8 methylation in eIF4E promoter region. Our results demonstrate the anti-cancer efficacy of ribavirin in CRC and suggest that the anti-cancer efficacy of ribavirin may be mediated by downregulating PRMT5 levels but not its enzymatic activity.