Mutant IDH1 activates JOSD2-YAP/TAZ in a non-classical manner to sustain intrahepatic cholangiocarcinoma cell growth
Gain of function mutations in isocitrate dehydrogenase 1 are one of the most common genetic lesions in intrahepatic cholangiocarcinoma (ICC). The mutant IDH1 (mIDH1) causes aberrant metabolic, epigenetic and differentiation process by converting a-ketoglutarate (a-KG) to onco-metabolite 2-hydroxyglutarate (2-HG). However, mIDH1 inhibitor ivosidenib appears much more effective in acute myeloid leukemia than that in ICC, suggesting that in addition to these common mechanisms, other pathways may be also involved. Our results indicated that mIDH1 exhibited high correlation of transcription profiles with JOSD2, a deubiquitinating enzyme reported to stabilize YAP/TAZ by our previous work. Further exploration suggested that mIDH1 up-regulated JOSD2 protein stability independent of 2-HG and couldn't be intervened by ivosidenib. The targeted silence of JOSD2 exhibited more potent anti-tumor effect in cells with mIDH1 than wild type cells. Together, this study may provide novel insights for understanding the tumor-promoting effects of mIDH1 to derive new therapeutic strategies. Overall design: RBE cells infected with scramble, shIDH1 or shJOSD2 lentivirus were performed RNA-sequencing. Each group has three replicates.