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Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells

Histone deacetylase inhibitors (HDACi) are emerging as anti-hepatocellular carcinoma (HCC) agents. However, the molecular mechanisms underlying HDACi-induced sensitization to oxidative stress and cell death of HCC remain elusive. We hypothesized that HDACi reduces the anti-oxidative stress capacity...

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Autores principales: Lee, Hae-Ahm, Chu, Ki-Back, Moon, Eun-Kyung, Quan, Fu-Shi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533003/
https://www.ncbi.nlm.nih.gov/pubmed/34679638
http://dx.doi.org/10.3390/antiox10101503
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author Lee, Hae-Ahm
Chu, Ki-Back
Moon, Eun-Kyung
Quan, Fu-Shi
author_facet Lee, Hae-Ahm
Chu, Ki-Back
Moon, Eun-Kyung
Quan, Fu-Shi
author_sort Lee, Hae-Ahm
collection PubMed
description Histone deacetylase inhibitors (HDACi) are emerging as anti-hepatocellular carcinoma (HCC) agents. However, the molecular mechanisms underlying HDACi-induced sensitization to oxidative stress and cell death of HCC remain elusive. We hypothesized that HDACi reduces the anti-oxidative stress capacity of HCC, rendering it more susceptible to oxidative stress and cell death. Change in the transcriptome of HCC was analyzed by RNA-seq and validated using real-time quantitative polymerase chain reaction (qPCR) and Western blot. Cell death of HCC was analyzed by fluorescence-activated cell sorting (FACS). Protein localization and binding on the target gene promoters were investigated by immunofluorescence (IF) and chromatin immunoprecipitation (ChIP), respectively. Glutathione peroxidase 8 (GPX8) was highly down-regulated in HCC upon oxidative stress and HDACi co-treatment. Oxidative stress and HDACi enhanced the expression and transcriptional activities of ER-stress-related genes. N-acetyl-cysteine (NAC) supplementation reversed the oxidative stress and HDACi-induced apoptosis in HCC. HDACi significantly enhanced the effect of ER stressors on HCC cell death. GPX8 overexpression reversed the activation of ER stress signaling and apoptosis induced by oxidative stress and HDACi. In conclusion, HDACi suppresses the expression of GPX8, which sensitizes HCC to ER stress and apoptosis by oxidative stress.
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spelling pubmed-85330032021-10-23 Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells Lee, Hae-Ahm Chu, Ki-Back Moon, Eun-Kyung Quan, Fu-Shi Antioxidants (Basel) Article Histone deacetylase inhibitors (HDACi) are emerging as anti-hepatocellular carcinoma (HCC) agents. However, the molecular mechanisms underlying HDACi-induced sensitization to oxidative stress and cell death of HCC remain elusive. We hypothesized that HDACi reduces the anti-oxidative stress capacity of HCC, rendering it more susceptible to oxidative stress and cell death. Change in the transcriptome of HCC was analyzed by RNA-seq and validated using real-time quantitative polymerase chain reaction (qPCR) and Western blot. Cell death of HCC was analyzed by fluorescence-activated cell sorting (FACS). Protein localization and binding on the target gene promoters were investigated by immunofluorescence (IF) and chromatin immunoprecipitation (ChIP), respectively. Glutathione peroxidase 8 (GPX8) was highly down-regulated in HCC upon oxidative stress and HDACi co-treatment. Oxidative stress and HDACi enhanced the expression and transcriptional activities of ER-stress-related genes. N-acetyl-cysteine (NAC) supplementation reversed the oxidative stress and HDACi-induced apoptosis in HCC. HDACi significantly enhanced the effect of ER stressors on HCC cell death. GPX8 overexpression reversed the activation of ER stress signaling and apoptosis induced by oxidative stress and HDACi. In conclusion, HDACi suppresses the expression of GPX8, which sensitizes HCC to ER stress and apoptosis by oxidative stress. MDPI 2021-09-22 /pmc/articles/PMC8533003/ /pubmed/34679638 http://dx.doi.org/10.3390/antiox10101503 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Hae-Ahm
Chu, Ki-Back
Moon, Eun-Kyung
Quan, Fu-Shi
Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells
title Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells
title_full Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells
title_fullStr Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells
title_full_unstemmed Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells
title_short Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells
title_sort glutathione peroxidase 8 suppression by histone deacetylase inhibitors enhances endoplasmic reticulum stress and cell death by oxidative stress in hepatocellular carcinoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533003/
https://www.ncbi.nlm.nih.gov/pubmed/34679638
http://dx.doi.org/10.3390/antiox10101503
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