期刊
CANCER PREVENTION RESEARCH
卷 16, 期 6, 页码 321-332出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1940-6207.CAPR-22-0384
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SAHA is able to regulate mitochondrial metabolism, DNA methylome reprogramming, and transcriptomic gene expression, thus inhibiting LPS-induced inflammatory responses in lung epithelial cells. SAHA treatment significantly alters the levels of metabolites involved in methionine, glutathione, and nicotinamide metabolism. Additionally, SAHA revokes differential methylation in certain gene promoter regions and abrogates the expression of proinflammatory cytokine genes.
Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor with anticancer effects via epigenetic and non-epigenetic mechanisms. The role of SAHA in metabolic rewiring and epigenomic reprogram-ming to inhibit pro-tumorigenic cascades in lung cancer remains unknown. In this study, we aimed to investigate the regulation of mitochondrial metabolism, DNA methylome reprogramming, and transcriptomic gene expression by SAHA in lipopolysaccharide (LPS)-induced inflammatory model of lung epithelial BEAS-2B cells. LC/MS was used for metabolomic analysis, while next-generation sequen-cing was done to study epigenetic changes. The metab-olomic study reveals that SAHA treatment significantly regulated methionine, glutathione, and nicotinamide metab-olism with alteration of the metabolite levels of methionine, S-adenosylmethionine, S-adenosylhomocysteine, glutathi-one, nicotinamide, 1-methylnicotinamide, and nicotinamide adenine dinucleotide in BEAS-2B cells. Epigenomic CpG methyl-seq shows SAHA revoked a list of differentially methylated regions in the promoter region of the genes, such as HDAC11, miR4509-1, and miR3191. Transcriptomic RNA sequencing (RNA-seq) reveals SAHA abrogated LPS-induced differentially expressed genes encoding proinflammatory cytokines, including interleukin 1a (IL1a), IL1b, IL2, IL6, IL24, and IL32. Integrative analysis of DNA methylome-RNA transcriptome displays a list of genes, of which CpG methyla-tion correlated with changes in gene expression. qPCR vali-dation of transcriptomic RNA-seq data shows that SAHA treatment significantly reduced the LPS-induced mRNA levels of IL1b, IL6, DNA methyltransferase 1 (DNMT1), and DNMT3A in BEAS-2B cells. Altogether, SAHA treatment alters the mitochondrial metabolism, epigenetic CpG methylation, and transcriptomic gene expression to inhibit LPS-induced inflammatory responses in lung epithelial cells, which may provide novel molecular targets to inhibit the inflammation component of lung carcinogenesis.
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