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Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation

Ferroptosis, a form of programmed cell death process driven by iron-dependent lipid peroxidation, plays an important role in tumor suppression. Although previous study showed that intracellular Merlin-Hippo signaling suppresses ferroptosis of epithelial tumor cells through the inactivation of YAP si...

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Autores principales: Qin, Yifei, Pei, Zhuo, Feng, Zhuan, Lin, Peng, Wang, Shijie, Li, Yong, Huo, Fei, Wang, Quancheng, Wang, Zhiping, Chen, Zhi-Nan, Wu, Jiao, Wang, Yi-Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717939/
https://www.ncbi.nlm.nih.gov/pubmed/34977009
http://dx.doi.org/10.3389/fcell.2021.751593
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author Qin, Yifei
Pei, Zhuo
Feng, Zhuan
Lin, Peng
Wang, Shijie
Li, Yong
Huo, Fei
Wang, Quancheng
Wang, Zhiping
Chen, Zhi-Nan
Wu, Jiao
Wang, Yi-Fei
author_facet Qin, Yifei
Pei, Zhuo
Feng, Zhuan
Lin, Peng
Wang, Shijie
Li, Yong
Huo, Fei
Wang, Quancheng
Wang, Zhiping
Chen, Zhi-Nan
Wu, Jiao
Wang, Yi-Fei
author_sort Qin, Yifei
collection PubMed
description Ferroptosis, a form of programmed cell death process driven by iron-dependent lipid peroxidation, plays an important role in tumor suppression. Although previous study showed that intracellular Merlin-Hippo signaling suppresses ferroptosis of epithelial tumor cells through the inactivation of YAP signaling, it remains elusive if the proto-oncogenic transcriptional co-activator YAP could serve as a potential biomarker to predict cancer cell response to ferroptosis-inducing therapies. In this study, we show that both total YAP staining and nuclear YAP staining were more prevalent in HCC tissues than in nontumorous regions. Compared to low-density HCC cells, high-density cells showed decreased nuclear localization of YAP and conferred significant resistance to ferroptosis. Oncogenic activation of YAP signaling by overexpression of YAP(S127A) mutant sensitized ferroptosis of HCC cells cultured in confluent density or in the 3D tumor spheroid model. Furthermore, we validated the lipoxygenase ALOXE3 as a YAP-TEAD target gene that contributed to YAP-promoted ferroptosis. Overexpression of ALOXE3 effectively increased the vulnerability of HCC cells to ferroptotic cell death. In an orthotopic mouse model of HCC, genetic activation of YAP rendered HCC cells more susceptible to ferroptosis. Finally, an overall survival assay further revealed that both a high expression of YAP and a low expression of GPX4 were correlated with increased survival of HCC patients with sorafenib treatment, which had been proven to be an inducer for ferroptosis by inhibition of the xc-amino acid antiporter. Together, this study unveils the critical role of intracellular YAP signaling in dictating ferroptotic cell death; it also suggests that pathogenic alterations of YAP signaling can serve as biomarkers to predict cancer cell responsiveness to future ferroptosis-inducing therapies.
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spelling pubmed-87179392021-12-31 Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation Qin, Yifei Pei, Zhuo Feng, Zhuan Lin, Peng Wang, Shijie Li, Yong Huo, Fei Wang, Quancheng Wang, Zhiping Chen, Zhi-Nan Wu, Jiao Wang, Yi-Fei Front Cell Dev Biol Cell and Developmental Biology Ferroptosis, a form of programmed cell death process driven by iron-dependent lipid peroxidation, plays an important role in tumor suppression. Although previous study showed that intracellular Merlin-Hippo signaling suppresses ferroptosis of epithelial tumor cells through the inactivation of YAP signaling, it remains elusive if the proto-oncogenic transcriptional co-activator YAP could serve as a potential biomarker to predict cancer cell response to ferroptosis-inducing therapies. In this study, we show that both total YAP staining and nuclear YAP staining were more prevalent in HCC tissues than in nontumorous regions. Compared to low-density HCC cells, high-density cells showed decreased nuclear localization of YAP and conferred significant resistance to ferroptosis. Oncogenic activation of YAP signaling by overexpression of YAP(S127A) mutant sensitized ferroptosis of HCC cells cultured in confluent density or in the 3D tumor spheroid model. Furthermore, we validated the lipoxygenase ALOXE3 as a YAP-TEAD target gene that contributed to YAP-promoted ferroptosis. Overexpression of ALOXE3 effectively increased the vulnerability of HCC cells to ferroptotic cell death. In an orthotopic mouse model of HCC, genetic activation of YAP rendered HCC cells more susceptible to ferroptosis. Finally, an overall survival assay further revealed that both a high expression of YAP and a low expression of GPX4 were correlated with increased survival of HCC patients with sorafenib treatment, which had been proven to be an inducer for ferroptosis by inhibition of the xc-amino acid antiporter. Together, this study unveils the critical role of intracellular YAP signaling in dictating ferroptotic cell death; it also suggests that pathogenic alterations of YAP signaling can serve as biomarkers to predict cancer cell responsiveness to future ferroptosis-inducing therapies. Frontiers Media S.A. 2021-12-16 /pmc/articles/PMC8717939/ /pubmed/34977009 http://dx.doi.org/10.3389/fcell.2021.751593 Text en Copyright © 2021 Qin, Pei, Feng, Lin, Wang, Li, Huo, Wang, Wang, Chen, Wu and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Qin, Yifei
Pei, Zhuo
Feng, Zhuan
Lin, Peng
Wang, Shijie
Li, Yong
Huo, Fei
Wang, Quancheng
Wang, Zhiping
Chen, Zhi-Nan
Wu, Jiao
Wang, Yi-Fei
Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation
title Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation
title_full Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation
title_fullStr Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation
title_full_unstemmed Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation
title_short Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation
title_sort oncogenic activation of yap signaling sensitizes ferroptosis of hepatocellular carcinoma via aloxe3-mediated lipid peroxidation accumulation
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717939/
https://www.ncbi.nlm.nih.gov/pubmed/34977009
http://dx.doi.org/10.3389/fcell.2021.751593
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