Role of histone deacetylase expression levels and activity in the inflammatory responses of patients with chronic hepatitis B

Zhang,Haiyue; Li,Xun; Zhang,Qian; Yang,Fan; Chu,Xiaogang; Zhang,Di; Wang,Luwen; Gong,Zuojiong

doi:10.3892/mmr.2017.6290

Role of histone deacetylase expression levels and activity in the inflammatory responses of patients with chronic hepatitis B

Authors:
- Haiyue Zhang
- Xun Li
- Qian Zhang
- Fan Yang
- Xiaogang Chu
- Di Zhang
- Luwen Wang
- Zuojiong Gong
View Affiliations

Affiliations: Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: March 7, 2017 https://doi.org/10.3892/mmr.2017.6290
Pages: 2744-2752

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Histone acetylation has been demonstrated to serve a pivotal role in numerous inflammatory diseases. The present study examined histone acetylation in patients with chronic hepatitis B (CHB) and CHB with liver failure by detecting histone deacetylase (HDAC) activity. Mice with acute liver failure (ALF) were treated with the HDAC inhibitor entinostat (MS275) and alterations in HDAC activity and pro‑inflammatory cytokine expression levels were detected. The effect of HDAC1 silencing on LPS-treated RAW264.7 murine macrophages was examined using specific small interfering RNA sequences, and the acetylation level of the non‑histone nuclear factor‑κB (NF‑κB) p65 subunit was additionally examined. The results demonstrated that serum levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin, and the expression levels of pro‑inflammatory cytokines, were significantly increased in patients with CHB. Aberrant histone acetylation and HDAC activity were identified in patients with CHB, with their levels associating with disease severity. MS275 treatment may decrease HDAC activity and inhibit the production of cytokines; however, acetylation levels of H3 and H4 were enhanced. Acetylation levels of NF‑κB p65 were decreased in lipopolysaccharide‑treated cells and ALF mice, and were promoted by MS275 treatment and HDAC1 silencing. In conclusion, alterations in HDAC activity and expression levels demonstrated a greater effect on inflammation compared with histone acetylation; therefore, the underlying mechanisms may be associated with the acetylation of non-histones. These results provide a potential novel therapeutic strategy for the treatment of CHB.

View Figures

View References

1	Lu Q, Qiu X, Hu N, Wen H, Su Y and Richardson BC: Epigenetics, disease, and therapeutic interventions. Ageing Res Rev. 5:449–467. 2006. View Article : Google Scholar : PubMed/NCBI
2	Portela A and Esteller M: Epigenetic modifications and human disease. Nat Biotechnol. 28:1057–1068. 2010. View Article : Google Scholar : PubMed/NCBI
3	Forsberg EC and Bresnick EH: Histone acetylation beyond promoters: Long-range acetylation patterns in the chromatin world. Bioessays. 23:820–830. 2001. View Article : Google Scholar : PubMed/NCBI
4	Wade PA: Transcriptional control at regulatory checkpoints by histone deacetylases: Molecular connections between cancer and chromatin. Hum Mol Genet. 10:693–698. 2001. View Article : Google Scholar : PubMed/NCBI
5	Merican I, Guan R, Amarapuka D, Alexander MJ, Chutaputti A, Chien RN, Hasnian SS, Leung N, Lesmana L, Phiet PH, et al: Chronic hepatitis B virus infection in Asian countries. J Gastroenterol Hepatol. 15:1356–1361. 2000. View Article : Google Scholar : PubMed/NCBI
6	The guideline of prevention and treatment for chronic hepatitis B (2010 version). Zhonghua Gan Zang Bing Za Zhi. 19:13–24. 2011.(In Chinese). PubMed/NCBI
7	Yim HJ and Lok AS: Natural history of chronic hepatitis B virus infection: What we knew in 1981 and what we know in 2005. Hepatology. 43:(2 Suppl 1). S173–S181. 2006. View Article : Google Scholar : PubMed/NCBI
8	Cantley MD and Haynes DR: Epigenetic regulation of inflammation: Progressing from broad acting histone deacetylase (HDAC) inhibitors to targeting specific HDACs. Inflammopharmacology. 21:301–307. 2013. View Article : Google Scholar : PubMed/NCBI
9	Gillespie J, Savic S, Wong C, Hempshall A, Inman M, Emery P, Grigg R and McDermott MF: Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum. 64:418–422. 2012. View Article : Google Scholar : PubMed/NCBI
10	Barnes PJ: Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol. 71:451–464. 2009. View Article : Google Scholar : PubMed/NCBI
11	Kim Y, Kim K, Park D, Lee E, Lee H, Lee YS, Choe J and Jeoung D: Histone deacetylase 3 mediates allergic skin inflammation by regulating expression of MCP1 protein. J Biol Chem. 287:25844–25859. 2012. View Article : Google Scholar : PubMed/NCBI
12	Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, de Silva HJ, Hamid SS, Jalan R, Komolmit P, et al: Acute-on-chronic liver failure: Consensus recommendations of the Asian pacific association for the study of the liver (APASL). Hepatol Int. 3:269–282. 2009. View Article : Google Scholar : PubMed/NCBI
13	Liaw YF, Kao JH, Piratvisuth T, Chan HL, Chien RN, Liu CJ, Gane E, Locarnini S, Lim SG, Han KH, et al: Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2012 update. Hepatol Int. 6:531–561. 2012. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Strahl BD and Allis CD: The language of covalent histone modifications. Nature. 403:41–45. 2000. View Article : Google Scholar : PubMed/NCBI
16	de Ruijter AJ, van Gennip AH, Caron HN, Kemp S and van Kuilenburg AB: Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem J. 370:737–749. 2003. View Article : Google Scholar : PubMed/NCBI
17	Chung S, Sundar IK, Yao H, Ho YS and Rahman I: Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of I{kappa}B kinases in mice: Impact on histone acetylation. Am J Physiol Lung Cell Mol Physiol. 299:L192–L203. 2010. View Article : Google Scholar : PubMed/NCBI
18	Natsume-Kitatani Y, Shiga M and Mamitsuka H: Genome-wide integration on transcription factors, histone acetylation and gene expression reveals genes co-regulated by histone modification patterns. Plos One. 6:e222812011. View Article : Google Scholar : PubMed/NCBI
19	Chung S, Sundar IK, Hwang JW, Yull FE, Blackwell TS, Kinnula VL, Bulger M, Yao H and Rahman I: NF-κB inducing kinase, NIK mediates cigarette smoke/TNFα-induced histone acetylation and inflammation through differential activation of IKKs. PLoS One. 6:e234882011. View Article : Google Scholar : PubMed/NCBI
20	Balasubramani A, Winstead CJ, Turner H, Janowski KM, Harbour SN, Shibata Y, Crawford GE, Hatton RD and Weaver CT: Deletion of a conserved cis-element in the Ifng locus highlights the role of acute histone acetylation in modulating inducible gene transcription. PLoS Genet. 10:e10039692014. View Article : Google Scholar : PubMed/NCBI
21	Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, Qian X, Mills E, Berghs SC, Carey N, et al: Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J. 409:581–589. 2008. View Article : Google Scholar : PubMed/NCBI
22	Cao W, Bao C, Padalko E and Lowenstein CJ: Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. J Exp Med. 205:1491–1503. 2008. View Article : Google Scholar : PubMed/NCBI
23	Li Y, Liu B, Zhao H, Sailhamer EA, Fukudome EY, Zhang X, Kheirbek T, Finkelstein RA, Velmahos GC, deMoya M, et al: Protective effect of suberoylanilide hydroxamic acid against LPS-induced septic shock in rodents. Shock. 32:517–523. 2009. View Article : Google Scholar : PubMed/NCBI
24	Zhang L, Wan J, Jiang R, Wang W, Deng H, Shen Y, Zheng W and Wang Y: Protective effects of trichostatin A on liver injury in septic mice. Hepatol Res. 39:931–938. 2009. View Article : Google Scholar : PubMed/NCBI
25	Flis S, Gnyszka A and Spławiński J: HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines. Biochem Biophys Res Commun. 387:336–341. 2009. View Article : Google Scholar : PubMed/NCBI
26	Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV and Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 325:834–840. 2009. View Article : Google Scholar : PubMed/NCBI
27	Spange S, Wagner T, Heinzel T and Krämer OH: Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 41:185–198. 2009. View Article : Google Scholar : PubMed/NCBI
28	Wang DY, Zou LP, Liu XJ, Zhu HG and Zhu R: Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis. Exp Mol Pathol. 99:399–408. 2015. View Article : Google Scholar : PubMed/NCBI
29	Tropberger P, Mercier A, Robinson M, Zhong W, Ganem DE and Holdorf M: Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. Proc Natl Acad Sci USA. 112:E5715–E5724. 2015. View Article : Google Scholar : PubMed/NCBI