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Interplay between c-Jun and TAp73α/β contributes to the apoptosis-survival balance

ABSTRACT: The p53-family member p73 functions in various cellular signaling pathways and can have tumor suppressor properties. Several isoforms of p73 exist that differ considerably in their function. Whereas the functions of the N-terminal isoforms (TA and ΔNp73) and their opposing pro- and anti-apoptotic roles became evident, the functional differences of the distinct C-terminal spliceforms of TAp73 have remained unclear. Here, we characterized the genomic binding sites for TAp73α and TAp73β and identified a specific p73 consensus binding-motif. Furthermore, an AP1 motif is strongly enriched close to binding sites for TAp73α. These AP1 motif-containing target genes are selectively upregulated by TAp73α, while their mRNA expression is repressed upon TAp73β induction. Recruitment of c-Jun to the respective AP1 sites was impaired upon TAp73β expression in part due to downregulation of c-Jun. We show that several of these AP1-site containing TAp73α-induced genes reduce on apoptosis-induction suggesting an underlying molecular mechanism for the observed functional differences between TAp73α and TAp73β.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15780 | GEO | 2011/03/01

SECONDARY ACCESSION(S): PRJNA116853

REPOSITORIES: GEO

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Project description:Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73 (TAp73) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis was used to identify TAp73-regulated gene sets. The effects of TAp73 were analyzed in monolayer cell culture, 3D-tumoroid and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 was significantly upregulated in HCC, and its high expression indicated poor patient survival. The induced expression of TAp73 caused landscape expression changes including genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. HCC cells overexpressing TAp73 had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73 upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings strongly suggest that TAp73 is a major promoter of malignant dedifferentiation of HCC cells Hepatocellular carcinoma (HCC) is a highly complex and heterogeneous type of cancer. Hepatocyte dedifferentiation is one of the important steps in the development of HCC. However, its molecular mechanisms are not well known. In this study, we report that TAp73 which is the major transcriptionally active form of p73 is overexpressed in HCC. Mechanically, TAp73 suppresses the expression of the hepatocyte markers including CYP3A4, AFP, ALB, HNF4a, while increasing the expression of several cholangiocyte markers in HCC cell lines. In conclusion, this report reveals a pro-oncogenic role for TAp73 in liver cancer.

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Interplay between c-Jun and TAp73α/β contributes to the apoptosis-survival balance

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