Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression.
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ABSTRACT:
SUBMITTER: Qian M
PROVIDER: S-EPMC8727894 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundActivation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); however, the expression pattern and the functional impact of its paralogue WW domain-containing transcription regulator 1 (WWTR1; synonym: TAZ) are not well described in different CCA subtypes.MethodsImmunohistochemical analysis of YAP and TAZ in iCCA and extrahepatic CCA (eCCA) cohorts was performed. YAP/TAZ shuttling and their functional impact on CCA cell lines were investigated. Target genes expression after combined YAP/TAZ inhibition was analyzed.ResultsImmunohistochemical analysis of iCCA and eCCA revealed YAP or TAZ positivity in up to 49.2%; however, oncogene co-expression was less frequent (up to 23%). In contrast, both proteins were jointly detectable in most CCA cell lines and showed nuclear/cytoplasmic shuttling in a cell density-dependent manner. Next to the pro-proliferative function of YAP/TAZ, both transcriptional co-activators cooperated in the regulation of a gene signature that indicated the presence of chromosomal instability (CIN). A correlation between YAP and the CIN marker phospho-H2A histone family member X (pH2AX) was particularly observed in tissues from iCCA and distal CCA (dCCA). The presence of the CIN genes in about 25% of iCCA was statistically associated with worse prognosis.ConclusionsYAP and TAZ activation is not uncoupled from cell density in CCA cells and both factors cooperatively contribute to proliferation and expression of CIN-associated genes. The corresponding group of CCA patients is characterized by CIN and may benefit from YAP/TAZ-directed therapies.
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Project description:The Hippo pathway effectors yes-associated protein (YAP) and WW domain containing transcription regulator 1 (TAZ/WWTR1) support tumor initiation and progression in various cancer types. However, to which extent YAP and TAZ cooperatively contribute to cholangiocarcinoma (CCA) development and progression is poorly understood. Our immunohistochemical studies showed that YAP and TAZ were expressed in different CCA subtypes. However, nuclear co-expression was not frequently detected. RNAinterference (RNAi) experiments illustrated that YAP and TAZ supported CCA cell viability. Comprehensive expression profiling of HUCCT-1 cells after combined silencing of YAP/TAZ revealed a potential impact on chromosomal instability.
2021-10-01 | GSE172135 | GEO