ENO1 promotes liver carcinogenesis through YAP1-dependent arachidonic acid metabolism

Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1. RNA immunoprecipitation sequencing (RIP-seq) analysis in HEK293T cells overexpressing ENO1, primary antibodies against ENO1 (11204-1-AP, Proteintech) were used in the RIP-seq assay. PLC cells with ENO1 or YAP1 knockdown were cultured with DMEM, then total RNA was extracted using Trizol Reagent followed by RNA-seq to identify the co-regulated genes by ENO1 and YAP1.