Cargando…
Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase
BACKGROUND: Lung adenocarcinoma is one of the most prevalent cancers while ferroptosis is crucial for cancer therapies. This study aims to investigate the function and mechanism of hepatic nuclear factor 4 alpha (HNF4A) in lung adenocarcinomas’ ferroptosis. MATERIALS AND METHODS: HNF4A expression in...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
PeerJ Inc.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10174064/ https://www.ncbi.nlm.nih.gov/pubmed/37180584 http://dx.doi.org/10.7717/peerj.15377 |
_version_ | 1785039957345173504 |
---|---|
author | Besskaya, Valeria Zhang, Huan Bian, Yunyi Liang, Jiaqi Bi, Guoshu Shan, Guangyao Zhan, Cheng Lin, Zongwu |
author_facet | Besskaya, Valeria Zhang, Huan Bian, Yunyi Liang, Jiaqi Bi, Guoshu Shan, Guangyao Zhan, Cheng Lin, Zongwu |
author_sort | Besskaya, Valeria |
collection | PubMed |
description | BACKGROUND: Lung adenocarcinoma is one of the most prevalent cancers while ferroptosis is crucial for cancer therapies. This study aims to investigate the function and mechanism of hepatic nuclear factor 4 alpha (HNF4A) in lung adenocarcinomas’ ferroptosis. MATERIALS AND METHODS: HNF4A expression in ferroptotic A549 cells was detected. Then HNF4A was knocked down in A549 cells while overexpressed in H23 cells. Cells with changed HNF4A expression were tested for cytotoxicity and the level of cellular lipid peroxidation. The expression of cytochrome P450 oxidoreductase (POR) expression was examined after HNF4A was knocked down or overexpressed. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) and dual-luciferase assays were performed to validate the regulation of HNF4A on POR. Finally, POR was restored in HNF4A-altered cells to check whether it restores the effect of HNF4A on ferroptosis. RESULTS: We found that HNF4A expression significantly decreased in the ferroptosis of A549 cells, and this change can be blocked by deferoxamine, an inhibitor of ferroptosis. Knockdown of HNF4A inhibited ferroptosis in A549 cells while overexpression of HNF4A promoted ferroptosis in H23 cells. We identified a key ferroptosis-related gene, POR serves as a potential target gene of HNF4A, whose expression was significantly changed in lung adenocarcinoma cells knocking down or overexpressing HNF4A. We demonstrated that HNF4A was bound to the POR’s promoter to enhance POR expression, and identified the binding sites via ChIP-qPCR and luciferase assays. Restoration of POR expression blocked the promoting effect of HNF4A on ferroptosis in lung adenocarcinoma. CONCLUSION: HNF4A promotes POR expression through binding to the POR’s promoter, and subsequently promotes the ferroptosis of lung adenocarcinoma. |
format | Online Article Text |
id | pubmed-10174064 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | PeerJ Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101740642023-05-12 Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase Besskaya, Valeria Zhang, Huan Bian, Yunyi Liang, Jiaqi Bi, Guoshu Shan, Guangyao Zhan, Cheng Lin, Zongwu PeerJ Biochemistry BACKGROUND: Lung adenocarcinoma is one of the most prevalent cancers while ferroptosis is crucial for cancer therapies. This study aims to investigate the function and mechanism of hepatic nuclear factor 4 alpha (HNF4A) in lung adenocarcinomas’ ferroptosis. MATERIALS AND METHODS: HNF4A expression in ferroptotic A549 cells was detected. Then HNF4A was knocked down in A549 cells while overexpressed in H23 cells. Cells with changed HNF4A expression were tested for cytotoxicity and the level of cellular lipid peroxidation. The expression of cytochrome P450 oxidoreductase (POR) expression was examined after HNF4A was knocked down or overexpressed. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) and dual-luciferase assays were performed to validate the regulation of HNF4A on POR. Finally, POR was restored in HNF4A-altered cells to check whether it restores the effect of HNF4A on ferroptosis. RESULTS: We found that HNF4A expression significantly decreased in the ferroptosis of A549 cells, and this change can be blocked by deferoxamine, an inhibitor of ferroptosis. Knockdown of HNF4A inhibited ferroptosis in A549 cells while overexpression of HNF4A promoted ferroptosis in H23 cells. We identified a key ferroptosis-related gene, POR serves as a potential target gene of HNF4A, whose expression was significantly changed in lung adenocarcinoma cells knocking down or overexpressing HNF4A. We demonstrated that HNF4A was bound to the POR’s promoter to enhance POR expression, and identified the binding sites via ChIP-qPCR and luciferase assays. Restoration of POR expression blocked the promoting effect of HNF4A on ferroptosis in lung adenocarcinoma. CONCLUSION: HNF4A promotes POR expression through binding to the POR’s promoter, and subsequently promotes the ferroptosis of lung adenocarcinoma. PeerJ Inc. 2023-05-08 /pmc/articles/PMC10174064/ /pubmed/37180584 http://dx.doi.org/10.7717/peerj.15377 Text en © 2023 Besskaya et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited. |
spellingShingle | Biochemistry Besskaya, Valeria Zhang, Huan Bian, Yunyi Liang, Jiaqi Bi, Guoshu Shan, Guangyao Zhan, Cheng Lin, Zongwu Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase |
title | Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase |
title_full | Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase |
title_fullStr | Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase |
title_full_unstemmed | Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase |
title_short | Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase |
title_sort | hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome p450 oxidoreductase |
topic | Biochemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10174064/ https://www.ncbi.nlm.nih.gov/pubmed/37180584 http://dx.doi.org/10.7717/peerj.15377 |
work_keys_str_mv | AT besskayavaleria hepaticnuclearfactor4alphapromotestheferroptosisoflungadenocarcinomaviatranscriptionalactivationofcytochromep450oxidoreductase AT zhanghuan hepaticnuclearfactor4alphapromotestheferroptosisoflungadenocarcinomaviatranscriptionalactivationofcytochromep450oxidoreductase AT bianyunyi hepaticnuclearfactor4alphapromotestheferroptosisoflungadenocarcinomaviatranscriptionalactivationofcytochromep450oxidoreductase AT liangjiaqi hepaticnuclearfactor4alphapromotestheferroptosisoflungadenocarcinomaviatranscriptionalactivationofcytochromep450oxidoreductase AT biguoshu hepaticnuclearfactor4alphapromotestheferroptosisoflungadenocarcinomaviatranscriptionalactivationofcytochromep450oxidoreductase AT shanguangyao hepaticnuclearfactor4alphapromotestheferroptosisoflungadenocarcinomaviatranscriptionalactivationofcytochromep450oxidoreductase AT zhancheng hepaticnuclearfactor4alphapromotestheferroptosisoflungadenocarcinomaviatranscriptionalactivationofcytochromep450oxidoreductase AT linzongwu hepaticnuclearfactor4alphapromotestheferroptosisoflungadenocarcinomaviatranscriptionalactivationofcytochromep450oxidoreductase |