AbstractIntracellular free cholesterol can be converted to cholesteryl ester and stored as lipid droplets through SOAT1-mediated esterification. Compelling evidence implicate targeting SOAT1 as a promising therapeutic strategy for cancer management. Herein, we demonstrate how targeting SOAT1 promotes YAP expression by elevating cellular cholesterol content in colon cancer cells. Results revealed that cholesterol alleviates the inhibitory effect of LRP6 on the Wnt/PCP pathway by impeding the

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... raction of LRP6 with FZD7. Subsequently, FZD7-mediated PCP signaling directly elevated YAP expression by activating RhoA. Nystatin-mediated cholesterol sequestration significantly inhibited YAP expression under SOAT1 inhibition. Moreover, nystatin synergized with the SOAT1 inhibitor avasimibe in suppressing the viability of colon cancer cells in vitro and in vivo. The present study provides new mechanistic insights into the functions of cholesterol metabolism on growth signaling pathways and implicates a novel strategy for cholesterol metabolic-targeted treatment of colon cancers.