Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded C... More
Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation and . Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression, which may provide a potential intervention target for YAP/TAZ-related CCA patients.
CCA, cholangiocarcinoma, Cholangiocarcinoma, DAB, 3,3-diaminobenzidine tetrahydrochloride chromogen, DUB, deubiquitinase, Deubiquitinase, FGFR, fibroblast growth factor receptor, FOLFOX, folinic acid, 5-FU and oxaliplatin, IDH1/2, isocitrate dehydrogenase 1/2, IHC, immunohistochemistry, IP, immunoprecipitation, JOSD2, KRAS, kirsten rat sarcoma 2 viral oncogene homolog, LATS1/2, large tumor suppressor kinase 1/2, MST1/2, mammalian Ste20-like kinases 1/2, OTUB2, otubain-2, PBS, phosphate-buffered saline, PDC, patient derived cell, PDX, patient-derived xenograft, RTV, relative tumor volume, SRB, sulforhodamine B, TAZ, transcriptional co-activator with PDZ-binding motif, TCGA, The Cancer Genome Atlas, USP9X/10/47, ubiquitin-specific peptidase 9X/10/47, YAP, Yes-associated protein, YAP/TAZ, YOD1, ubiquitin thioesterase OTU1, rhJOSD2, recombinant human JOSD2, shRNA, specific hairpin RNA
