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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
Suberoylanilide hydroxamic acid upregulates reticulophagy receptor expression and promotes cell death in hepatocellular carcinoma cells
Jia-Yao Li, Tian Tian, Bing Han, Ting Yang, Yi-Xin Guo, Jia-Yu Wu, Yu-Si Chen, Qin Yang, Ru-Jia Xie
Jia-Yao Li, Bing Han, Ting Yang, Yi-Xin Guo, Jia-Yu Wu, Yu-Si Chen, Qin Yang, Ru-Jia Xie, Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
Jia-Yao Li, Bing Han, Ting Yang, Yi-Xin Guo, Jia-Yu Wu, Yu-Si Chen, Qin Yang, Ru-Jia Xie, Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
Tian Tian, Department of Eugenic Genetics, Guiyang Maternal and Child Health Care Hospital, Guiyang 550003, Guizhou Province, China
Author contributions: Xie RJ and Yang Q contributed to the experimental conception and design; Li JY, Tian T, and Han B conducted the experiments; Yang T and Guo YX collected and assembled the experimental data; Li JY, Chen YS, and Wu JY contributed to data analysis and interpretation; Li JY and Xie RJ wrote the article; All authors approved the final manuscript. Li JY, Tian T, and Han B contributed equally to this work.
Supported by the National Natural Science Foundation of China, No. 82260127; Guizhou Provincial Science and Technology Projects, No. Qiankehe Jichu-ZK[2021]365 and Qiankehe Jichu-ZK[2021]364; National Natural Science Foundation Cultivation Project of Guizhou Medical University, No. 20NSP016; Guizhou Provincial Natural Science Foundation, No. [2021]4029 and [2022]4017; and Science and Technology Foundation of Guizhou Provincial Health Commission, No. gzwjkj2019-1-102.
Institutional review board statement: This study did not involve human subjects or living animals.
Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article.
Data sharing statement: The data used to support the findings of this study are available from the corresponding author at 592153968@qq.com upon request.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Ru-Jia Xie, MD, Academic Research, Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Dongqing Road, Guiyang 550025, Guizhou Province, China. 592153968@qq.com
Received: March 23, 2023
Peer-review started: March 23, 2023
First decision: June 17, 2023
Revised: July 15, 2023
Accepted: August 15, 2023
Article in press: August 15, 2023
Published online: September 14, 2023
ARTICLE HIGHLIGHTS
Research background
Suberoylanilide hydroxamic acid (SAHA) has been demonstrated to trigger multiple forms of cell death in hepatocellular carcinoma (HCC). Family with sequence similarity 134 member B (FAM134B), a reticulophagy receptor, has been recognized as a cancer suppressor protein in multiple tumors, including HCC. However, few researchers have focused on the relationship between reticulophagy and SAHA-induced HCC cell death.
Research motivation
Reticulophagy is involved in a variety of human cancer pathologies. However, its specific function in the modulation of SAHA-initiated HCC cell death remains unproven.
Research objectives
To validate the potential regulatory mechanisms of the FAM134B-mediated reticulophagy in SAHA-induced HCC cell death.
Research methods
The proliferation, apoptosis, and cell cycle of SAHA-treated Huh7 and MHCC97L cells were quantified using cell counting kit-8 and flow cytometry. The migration and invasion of Huh7 and MHCC97L cells were measured using the transwell assay. Proteins related to the reticulophagy pathway, mitochondria-endoplasmic reticulum contact sites, intrinsic mitochondrial apoptosis, and histone H4K16 acetylation were detected using western blotting. ER and lysosome co-localization, and mitochondrial Ca2+ levels were observed via confocal microscopy. Autophagy-mediated cell death was validated through Hoechst33342 staining and propidium iodide colocalization. The enrichment of histone H4 lysine 16 acetylation in the FAM134B promoter region was determined using chromatin immunoprecipitation.
Research results
SAHA treatment augmented the expression of proteins related to the reticulophagy pathway and enhanced the level of reticulophagy in HCC cells. Chromatin immunoprecipitation experiments confirmed that SAHA regulated FAM134B expression by increasing the histone H4 lysine 16 acetylation in the FAM134B promoter region. SAHA interfered with Ca2+ homeostasis in HCC cells and upregulated the expression of autocrine motility factor receptor-related and mitochondria-endoplasmic reticulum contact sites-related proteins. Furthermore, SAHA reduced mitochondrial membrane potential and aggravated the activation of the reticulophagy-mediated mitochondrial apoptosis pathway and HCC cell death.
Research conclusions
SAHA stimulated excessive reticulophagy and induced autophagy-mediated cell death, which acted synergistically with the mitochondria-dependent apoptotic pathway to facilitate HCC cell death.
Research perspectives
FAM134B-induced reticulophagy may further provide a novel avenue for more effective interventions in HCC treatment. Our results confirmed that reticulophagy participates in SAHA-induced apoptosis and autophagy-mediated cell death in HCC cells, where SAHA-induced regulation of FAM134B expression via histone H4 lysine 16 is the key to HCC cell death.
