R-2HG downregulates ERα to inhibit cholangiocarcinoma via the FTO/m6A-methylated ERα/miR16-5p/YAP1 signal pathway
Yuan Gao, Xiwu Ouyang, Li Zuo, Yao Xiao, Yin Sun, Chawnshang Chang, Xihu Qin, Shuyuan Yeh
Abstract
-methyladenosine (m6A) to methylate the mRNA of ERα, and consequently decrease protein translation of the ERα. Further mechanistic studies revealed that ERα could transcriptionally suppress miR-16-5p expression, which could then increase YAP1 expression due to the reduced miR-16-5p binding to the 3' UTR of YAP1. Furthermore, data from the pre-clinical animal model with implantation of IDH1R132H QBC939 cells demonstrated that R-2HG generated by the IDH1 mutation could downregulate ERα and YAP1 to suppress CCA tumor growth. Taken together, our new findings suggested that IDH1 mutation-induced R-2HG could suppress CCA growth via regulating the FTO/m6A-methylated ERα/miR16-5p/YAP1 signaling pathway. Upregulating R-2HG or downregulating the ERα signal by short hairpin RNA ERα (shERα) or antiestrogen could be effective strategies to inhibit CCA.