Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma

Marcell Tóth,Niels Grabe,Julian Schmitt ,L Thiess ,Sofia M.e Weiler ,Bruno Köhler ,Arianeb Mehrabi,Christoph Springfeld,Carolina De La Torre,Lilija Wehling,Thomas Albrecht,Stephanie Roessler,Carsten Sticht,Melina Rausch,Peter Schirmacher,Lea Duwe,Fabian Rose,Jesper B Andersen,Benjamin Goeppert,Yakup Kulu,Kai Breuhahn

doi:10.1186/s12885-021-08794-5

Abstract

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.

Highlights

Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma; 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
Controlled by cellcell contact, cell density and cell polarity, inactivation of a central kinase cassette consisting of mammalian STE20-like protein kinase (MST)-1/2 and large tumor suppressor kinase (LATS)-1/2 is leading to YAP/TAZ hypophosphorylation and nuclear translocation followed by their interaction with transcription factors such as TEA domain transcription factors (TEADs) family members or forkhead box M1 (FOXM1) [2, 3]
Patient cohort and tissue microarray (TMA) Tissue samples organized on three TMAs and clinical data derived from 152 intrahepatic cholangiocarcinoma (iCCA) patients, 155 pCCA patients and 126 distal CCA (dCCA) patients were used for this study as previously described (Supplementary Table S1) [16]

Summary

Introduction

Activation of the oncogene yes-associated protein (YAP) is frequently detected in intrahepatic cholangiocarcinoma (iCCA); 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. The complex consisting of YAP and transcription factors promotes the expression of genes involved in DNA replication, cell cycle regulation, chromosomal segregation, and in the control of cellular stemness. In this context, YAP-dependent proliferation of liver cells is leading to the accumulation of mutations and the induction of chromosomal instability (CIN) [3]. Recent data demonstrated that TAZ cooperates with YAP in HCC progression [7]

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