TY - JOUR
T1 - Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells
AU - Wang, Lujing
AU - Shannar, Ahmad Abdel Fat
AU - Wu, Renyi
AU - Chou, Pochung
AU - Sarwar, Md Shahid
AU - Kuo, Hsiao chen
AU - Peter, Rebecca Mary
AU - Wang, Yujue
AU - Su, Xiaoyang
AU - Kong, Ah Ng
N1 - Funding Information:
The authors thank all the members of Professor Ah‐Ng Kong's laboratory for their invaluable discussion and technical support for preparation of this manuscript. This work was supported in part by institutional funds and by R01 AT009152 from the National Center for Complementary and Integrative Health (NCCIH), and P30 ES005022 from the National Institute of Environmental Health (NIEHS).
Publisher Copyright:
© 2022 Wiley-VCH GmbH.
PY - 2022/6
Y1 - 2022/6
N2 - Scope: Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling, and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear. Methods and results: Sodium butyrate (NaB) dose-dependently inhibits the growth of CRC HCT116 cells. NaB inhibits NRF2/NRF2-target genes and blocks NRF2-ARE signaling. NaB increases NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 are correlated with their promoters’ CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulates the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B, and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics. Conclusion: B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic, and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model.
AB - Scope: Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling, and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear. Methods and results: Sodium butyrate (NaB) dose-dependently inhibits the growth of CRC HCT116 cells. NaB inhibits NRF2/NRF2-target genes and blocks NRF2-ARE signaling. NaB increases NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 are correlated with their promoters’ CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulates the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B, and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics. Conclusion: B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic, and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model.
KW - colorectal cancer
KW - epigenetic
KW - metabolomics
KW - nuclear factor erythroid-2 like 2 (NRF2)
KW - sodium butyrate
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U2 - 10.1002/mnfr.202200028
DO - 10.1002/mnfr.202200028
M3 - Article
C2 - 35429118
AN - SCOPUS:85128863259
SN - 1613-4125
VL - 66
JO - Die Nahrung
JF - Die Nahrung
IS - 12
M1 - 2200028
ER -