Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis.
Acyltransferases
/ genetics
Aged
Animals
Carcinoma, Hepatocellular
/ genetics
Cell Cycle Proteins
/ genetics
Female
Hepatitis B
/ complications
Hepatitis B virus
/ isolation & purification
Humans
Liver Neoplasms
/ genetics
Male
Mice
Mice, Knockout
Transcription Factors
/ genetics
YAP-Signaling Proteins
/ genetics
Cell Cycle
Hepatocellular Carcinoma
TAZ
YAP
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2021
2021
Historique:
received:
22
07
2020
revised:
11
11
2020
accepted:
12
11
2020
pubmed:
25
11
2020
medline:
8
3
2022
entrez:
24
11
2020
Statut:
ppublish
Résumé
Yes-associated protein (YAP) and its paralog transcriptional co-activator with post synaptic density protein, drosophila disc large tumor suppressor and zonula occludens-1-binding motif (TAZ) are 2 co-activators downstream of Hippo tumor-suppressor cascade. Both have been implicated in the development of hepatocellular carcinoma (HCC). However, whether YAP and TAZ have distinct or overlapping functions during hepatocarcinogenesis remains unknown. Expression patterns of YAP and TAZ were analyzed in human HCC samples. The requirement of Yap and/or Taz in protein kinase B (Akt)/ neuroblastoma RAS viral oncogene homolog (NRas) -driven liver tumorigenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout mice. Transcriptional programs regulated by YAP and/or TAZ were identified via RNA sequencing. We found that in human HCC samples, an almost ubiquitous activation of YAP or TAZ occurs, underlying their role in this tumor type. Intriguingly, 70% of HCC samples showed only nuclear YAP or TAZ immunoreactivity. In the Akt/NRas liver tumor model, where nuclear Yap and Taz can be detected readily, deletion of Yap or Taz alone only mildly delayed liver tumor development, whereas their concomitant ablation strongly inhibited tumor cell proliferation and significantly suppressed Akt/NRas-driven hepatocarcinogenesis. In HCC cell lines, silencing of either YAP or TAZ led to decreased expression of both overlapping and distinct sets of genes, with the most prominent gene signatures related to cell-cycle progression and DNA replication. YAP and TAZ have overlapping and distinct roles in hepatocarcinogenesis. HCCs may display unique activation of YAP or TAZ, thus relying on either YAP or TAZ for their growth.
Sections du résumé
BACKGROUND & AIMS
Yes-associated protein (YAP) and its paralog transcriptional co-activator with post synaptic density protein, drosophila disc large tumor suppressor and zonula occludens-1-binding motif (TAZ) are 2 co-activators downstream of Hippo tumor-suppressor cascade. Both have been implicated in the development of hepatocellular carcinoma (HCC). However, whether YAP and TAZ have distinct or overlapping functions during hepatocarcinogenesis remains unknown.
METHODS
Expression patterns of YAP and TAZ were analyzed in human HCC samples. The requirement of Yap and/or Taz in protein kinase B (Akt)/ neuroblastoma RAS viral oncogene homolog (NRas) -driven liver tumorigenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout mice. Transcriptional programs regulated by YAP and/or TAZ were identified via RNA sequencing.
RESULTS
We found that in human HCC samples, an almost ubiquitous activation of YAP or TAZ occurs, underlying their role in this tumor type. Intriguingly, 70% of HCC samples showed only nuclear YAP or TAZ immunoreactivity. In the Akt/NRas liver tumor model, where nuclear Yap and Taz can be detected readily, deletion of Yap or Taz alone only mildly delayed liver tumor development, whereas their concomitant ablation strongly inhibited tumor cell proliferation and significantly suppressed Akt/NRas-driven hepatocarcinogenesis. In HCC cell lines, silencing of either YAP or TAZ led to decreased expression of both overlapping and distinct sets of genes, with the most prominent gene signatures related to cell-cycle progression and DNA replication.
CONCLUSIONS
YAP and TAZ have overlapping and distinct roles in hepatocarcinogenesis. HCCs may display unique activation of YAP or TAZ, thus relying on either YAP or TAZ for their growth.
Identifiants
pubmed: 33232824
pii: S2352-345X(20)30187-9
doi: 10.1016/j.jcmgh.2020.11.008
pmc: PMC7903139
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
Transcription Factors
0
YAP-Signaling Proteins
0
YY1AP1 protein, human
0
Yap1 protein, mouse
0
Acyltransferases
EC 2.3.-
tafazzin protein, mouse
EC 2.3.-
TAFAZZIN protein, human
EC 2.3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1095-1117Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK026743
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190606
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204586
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239251
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.