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.
Highlights
The global hepatocellular carcinoma (HCC) incidence has been on the rise over the past decade, and the mortality associated with it has been reported to be the second highest among all cancer-related deaths [1]
In 2007, based on the positive results acquired from the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, sorafenib was approved by the US Food and Drug Administration (FDA) as a first-line treatment option for advanced HCC [5]
We demonstrated that Histone deacetylase inhibitors (HDACi) treatment sensitizes HCC cells to oxidative stress and cell cycle arrest [20]
Summary
The global hepatocellular carcinoma (HCC) incidence has been on the rise over the past decade, and the mortality associated with it has been reported to be the second highest among all cancer-related deaths [1]. Since clinical manifestations in the early stages of HCC tend to be asymptomatic and are difficult to discern, most HCC patients are diagnosed at the advanced stage, which limits available treatment options [3]. While therapeutic interventions are possible, chemoresistance development in HCC has rendered the drugs ineffective [4]. In 2007, based on the positive results acquired from the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, sorafenib was approved by the US Food and Drug Administration (FDA) as a first-line treatment option for advanced HCC [5]. Several other drugs, such as lenvatinib, regorafenib, and cabozantinib, have been developed and approved by the FDA for treating unresectable HCC [6].
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