Back to Search Start Over

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

Authors :
Hae-Ahm Lee
Ki-Back Chu
Eun-Kyung Moon
Fu-Shi Quan
Source :
Antioxidants, Vol 10, Iss 10, p 1503 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
20763921
Volume :
10
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Antioxidants
Publication Type :
Academic Journal
Accession number :
edsdoj.76e12a9fe1247608d09c71d528c11bf
Document Type :
article
Full Text :
https://doi.org/10.3390/antiox10101503