PMID- 36867722 OWN - NLM STAT- MEDLINE DCOM- 20230602 LR - 20231202 IS - 1940-6215 (Electronic) IS - 1940-6207 (Print) IS - 1940-6215 (Linking) VI - 16 IP - 6 DP - 2023 Jun 1 TI - Metabolomic, DNA Methylomic, and Transcriptomic Profiling of Suberoylanilide Hydroxamic Acid Effects on LPS-Exposed Lung Epithelial Cells. PG - 321-332 LID - 10.1158/1940-6207.CAPR-22-0384 [doi] AB - 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 reprogramming 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 sequencing was done to study epigenetic changes. The metabolomic study reveals that SAHA treatment significantly regulated methionine, glutathione, and nicotinamide metabolism with alteration of the metabolite levels of methionine, S-adenosylmethionine, S-adenosylhomocysteine, glutathione, 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 1alpha (IL1alpha), IL1beta, IL2, IL6, IL24, and IL32. Integrative analysis of DNA methylome-RNA transcriptome displays a list of genes, of which CpG methylation correlated with changes in gene expression. qPCR validation of transcriptomic RNA-seq data shows that SAHA treatment significantly reduced the LPS-induced mRNA levels of IL1beta, 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. PREVENTION RELEVANCE: Inflammation increases the risk of lung cancer and blocking inflammation could reduce the incidence of lung cancer. Herein, we demonstrate that histone deacetylase inhibitor suberoylanilide hydroxamic acid regulates metabolic rewiring and epigenetic reprogramming to attenuate lipopolysaccharide-driven inflammation in lung epithelial cells. CI - (c)2023 American Association for Cancer Research. FAU - Chou, Pochung Jordan AU - Chou PJ AUID- ORCID: 0000-0001-8783-5577 AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. FAU - Sarwar, Md Shahid AU - Sarwar MS AUID- ORCID: 0000-0003-0093-5263 AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. FAU - Wang, Lujing AU - Wang L AUID- ORCID: 0000-0001-7413-2223 AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. FAU - Wu, Renyi AU - Wu R AUID- ORCID: 0000-0001-8717-9944 AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. FAU - Li, Shanyi AU - Li S AUID- ORCID: 0000-0003-0208-0481 AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. FAU - Hudlikar, Rasika R AU - Hudlikar RR AUID- ORCID: 0000-0002-6782-4173 AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. FAU - Wang, Yujue AU - Wang Y AUID- ORCID: 0000-0001-7088-1729 AD - Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. AD - Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey. FAU - Su, Xiaoyang AU - Su X AUID- ORCID: 0000-0001-8081-1396 AD - Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. AD - Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey. FAU - Kong, Ah-Ng AU - Kong AN AUID- ORCID: 0000-0002-9273-4217 AD - Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey. LA - eng GR - P30 CA072720/CA/NCI NIH HHS/United States GR - P30 ES005022/ES/NIEHS NIH HHS/United States GR - R01 AT009152/AT/NCCIH NIH HHS/United States GR - R01 CA200129/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Cancer Prev Res (Phila) JT - Cancer prevention research (Philadelphia, Pa.) JID - 101479409 RN - 58IFB293JI (Vorinostat) RN - 0 (Lipopolysaccharides) RN - 0 (Interleukin-6) RN - 0 (Hydroxamic Acids) RN - 0 (Histone Deacetylase Inhibitors) RN - 9007-49-2 (DNA) RN - GAN16C9B8O (Glutathione) RN - AE28F7PNPL (Methionine) SB - IM MH - Humans MH - Vorinostat MH - *Lipopolysaccharides/pharmacology MH - Interleukin-6 MH - Transcriptome MH - Hydroxamic Acids/pharmacology MH - Histone Deacetylase Inhibitors/pharmacology MH - Lung MH - Inflammation MH - DNA MH - *Lung Neoplasms MH - Epithelial Cells MH - Glutathione/genetics MH - Methionine PMC - PMC10238674 MID - NIHMS1881771 COIS- Conflicts of Interest: The authors declare no potential conflicts of interest EDAT- 2023/03/04 06:00 MHDA- 2023/06/02 06:42 PMCR- 2023/12/01 CRDT- 2023/03/03 14:32 PHST- 2022/08/23 00:00 [received] PHST- 2022/12/12 00:00 [revised] PHST- 2023/03/01 00:00 [accepted] PHST- 2023/06/02 06:42 [medline] PHST- 2023/03/04 06:00 [pubmed] PHST- 2023/03/03 14:32 [entrez] PHST- 2023/12/01 00:00 [pmc-release] AID - 726440 [pii] AID - 10.1158/1940-6207.CAPR-22-0384 [doi] PST - ppublish SO - Cancer Prev Res (Phila). 2023 Jun 1;16(6):321-332. doi: 10.1158/1940-6207.CAPR-22-0384.