Journal of Clinical and Translational Hepatology

Journal of Clinical and Translational Hepatology

Wednesday, 08 / 04 / 2021

Articles

Abstract

ORIGINAL ARTICLE

Roles of SET7/9 and LSD1 in the Pathogenesis of Arsenic-induced Hepatocyte Apoptosis

Bing Han1,2,# , Yi Yang1,2,# , Lei Tang3,#, Qin Yang1,2 and Rujia Xie1,2,*

1  Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
2  Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, China
3  Medical College of Guizhou University, Guiyang, Guizhou, China
#These authors contributed equally to this study.
*Correspondence to: Rujia Xie, Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550000, China. ORCID:  https://orcid.org/0000-0001-5991-2678 . Tel: +86-13985441220, E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

Journal of Clinical and Translational Hepatology 2021;9(3):364-372 DOI: 10.14218/JCTH.2020.00185
Received: December 28, 2020 Accepted: March 11, 2021 Published online: April 16, 2021

Abstract

Background and Aims:Multiple regulatory mechanisms play an important role in arsenic-induced liver injury. To investigate whether histone H3 lysine 4 (H3K4) methyltransferase (SET7/9) and histone H3K4 demethyltransferase (LSD1/KDM1A) can regulate endoplasmic reticulum stress (ERS)-related apoptosis by modulating the changes of H3K4 methylations in liver cells treated with arsenic.

Methods:Apoptosis, proliferation and cell cycles were quantified by flow cytometry and real-time cell analyzer. The expression of ERS- and epigenetic-related proteins was detected by Western blot analysis. The antisense SET7/9 expression vector and the overexpressed LSD1 plasmid were used for transient transfection of LO2 cells. The effects of NaAsO2 on the methylation of H3 in the promoter regions of 78 kDa glucose-regulated protein, activating transcription factor 4 and C/EBP-homologous protein were evaluated by chromatin immunoprecipitation assay.

Results:The protein expression of LSD1 (1.25±0.08 vs. 1.77±0.08, p=0.02) was markedly decreased by treatment with 100 µM NaAsO2, whereas the SET7/9 (0.68±0.05 vs. 1.10±0.13, p=0.002) expression level was notably increased, which resulted in increased H3K4me1/2 (0.93±0.64, 1.19±0.22 vs. 0.71±0.13, 0.84±0.13, p=0.03 and p=0.003). After silencing SET7/9 and overexpressing LSD1 by transfection, apoptosis rate (in percentage: 3.26±0.34 vs. 7.04±0.42, 4.80±0.32 vs. 7.52±0.38, p=0.004 and p=0.02) was significantly decreased and proliferation rate was notably increased, which is reversed after inhibiting LSD1 (in percentage: 9.31±0.40 vs. 7.52±0.38, p=0.03). Furthermore, the methylation levels of H3 in the promoter regions of GRP78 (20.80±2.40 vs. 11.75±2.47, 20.46±2.23 vs. 14.37±0.91, p=0.03 and p=0.01) and CHOP (48.67±4.04 vs. 16.67±7.02, 59.33±4.51 vs. 20.67±3.06, p=0.004 and p=0.001) were significantly increased in LO2 cells exposed to 100 µM NaAsO2 for 24 h.

Conclusions:Histone methyltransferase SET7/9 and histone demethyltransferase LSD1 jointly regulate the changes of H3K4me1/me2 levels in arsenic-induced apoptosis. NaAsO2 induces apoptosis in LO2 cells by activating the ERS-mediated apoptotic signaling pathway, at least partially by enhancing the methylation of H3 on the promoter regions of ERS-associated genes, including GRP78 and CHOP.

Keywords

Arsenic, SET7/9, LSD1, H3K4me1/2, ER stress

Journal of Clinical and Translational Hepatology 2021 vol. 9, 364-372  [ Html  ] [ PDF Full-text ]

© 2021 Authors. This is an Open Access article distributed under the terms of the  Creative Commons Attribution-Noncommercial 4.0 License(CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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