期刊
MOLECULAR THERAPY-ONCOLYTICS
卷 23, 期 -, 页码 65-81出版社
CELL PRESS
DOI: 10.1016/j.omto.2021.06.017
关键词
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资金
- University of Rochester George Whipple Endowment
- National Natural Science Foundation of China [81672469]
- Division of General Surgery of Changzhou
Mutations in Isocitrate dehydrogenase (IDH) increase production of (R)-2-hy-droxyglutarate (R-2HG), which has been shown to suppress cholangiocarcinoma (CCA) growth by regulating the FTO/m6A-methylated ER alpha/miR16-5p/YAP1 signaling pathway. Upregulating R-2HG or downregulating ER alpha may be effective strategies to inhibit CCA.
Isocitrate dehydrogenase (IDH) mutations increase (R)-2-hy-droxyglutarate (R-2HG) production; however, functional mechanisms of R-2HG in regulating cholangiocarcinoma (CCA) development remain to be further investigated. We first applied the CRISPR-Cas9 gene-editing system to create IDH1R132H-mutated CCA cells. Interestingly, our data showed that R-2HG could function through downregulating estrogen receptor alpha (ER alpha) and Yes-associated protein 1 (YAP1) pathways to decrease CCA growth. Detailed mechanistic studies revealed that R-2HG could target and degrade the fat mass and obesity-associated protein (FTO), the first identified mRNA demethylase. This reduced FTO can increase the N-6-methyladenosine (m6A) to methylate the mRNA of ER alpha, and consequently decrease protein translation of the ER alpha. Further mechanistic studies revealed that ER alpha could transcriptionally suppress miR-16-5p expression, which could then increase YAP1 expression due to the reduced miR-16-5p binding to the 30 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 ER alpha 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 ER alpha/miR16-5p/YAP1 signaling pathway. Upregulating R-2HG or downregulating the ER alpha signal by short hairpin RNA ERa (shER alpha) or antiestrogen could be effective strategies to inhibit CCA.
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