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Cited by 789Gut microbiota and healthReceptor Mechanisms and SignalingHistone Deacetylase Inhibitors Research

GPR109A Is a G-protein–Coupled Receptor for the Bacterial Fermentation Product Butyrate and Functions as a Tumor Suppressor in Colon

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Thangaraju, Muthusamy, Cresci, Gail A., Liu, Kebin, Ananth, Sudha, Gnanaprakasam, Jaya P., Browning, Darren D., Mellinger, John D., Smith, Sylvia B. +4 more·2009·Cancer Research
DOI 10.1158/0008-5472.can-08-4466PMC PMC3747834

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Abstract

Short-chain fatty acids, generated in colon by bacterial fermentation of dietary fiber, protect against colorectal cancer and inflammatory bowel disease. Among these bacterial metabolites, butyrate is biologically most relevant. GPR109A is a G-protein–coupled receptor for nicotinate but recognizes butyrate with low affinity. Millimolar concentrations of butyrate are needed to activate the receptor. Although concentrations of butyrate in colonic lumen are sufficient to activate the receptor maximally, there have been no reports on the expression/function of GPR109A in this tissue. Here we show that GPR109A is expressed in the lumen-facing apical membrane of colonic and intestinal epithelial cells and that the receptor recognizes butyrate as a ligand. The expression of GPR109A is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of GPR109A involves DNA methylation directly or indirectly. Reexpression of GPR109A in colon cancer cells induces apoptosis, but only in the presence of its ligands butyrate and nicotinate. Butyrate is an inhibitor of histone deacetylases, but apoptosis induced by activation of GPR109A with its ligands in colon cancer cells does not involve inhibition of histone deacetylation. The primary changes in this apoptotic process include down-regulation of Bcl-2, Bcl-xL, and cyclin D1 and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-κB activation in normal and cancer colon cell lines as well as in normal mouse colon. These studies show that GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon. [Cancer Res 2009;69(7):2826–32]

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  • Butyrate activates the niacin receptor hydroxycarboxylic acid receptor 2 and the olfactory receptor OR51E1.

    “A lesser-known colonic GPCR activated by butyrate is the receptor for niacin: hydroxycarboxylic acid receptor 2 (Thangaraju et al., 2009).Another receptor activated by butyrate is the olfactory receptor family 51 subfamily E member 1 (OR51E1 for humans, olfactory receptor 558 -Olfr558 for mice) (Priori et al., 2015).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Thangaraju et al., 2009

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Authors
Thangaraju, M., Cresci, G. A., Liu, K., Ananth, S., Gnanaprakasam, J. P., Browning, D. D., Mellinger, J. D., Smith, S. B., Digby, G. J., Lambert, N. A., Prasad, P. D., & Ganapathy, V.
Affiliations
  • 1Biochemistry and Molecular Biology, Departments of
  • 2Surgery,
  • 3Cellular Biology and Anatomy, and
  • Augusta University (US)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2009-04-01
Volume
69
Issue
7
Pages
2826-2832
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-08-4466
PMC
PMC3747834
OpenAlex
W2145159460
Cited by
789
References
3
Citations by year
2026: 51 · 2025: 81 · 2024: 59 · 2023: 72 · 2022: 82 · 2021: 91 · 2020: 53 · 2019: 54 · 2018: 61 · 2017: 38 · 2016: 31 · 2015: 19 · 2014: 22 · 2013: 23 · 2012: 19
FWCI
6.99
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA133085, R21CA152396)
  • National Institute of General Medical Sciences (R01GM078319)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Keywords
GPR109A, butyrate, G protein-coupled receptors, short-chain fatty acids, colon cancer, tumor suppression, DNA methylation, apoptosis, nicotinate, histone deacetylase inhibition, Bcl-2, Bcl-xL, cyclin D1, death receptor signaling, NF-κB, colonic epithelium
MeSH terms
Amino Acid Sequence, Animals, Butyrates, Colon, Colonic Neoplasms, Fermentation, Humans, Molecular Sequence Data, Niacin, Receptors, Nicotinic, RNA, Messenger, Transfection, NF-kappa B, Apoptosis, DNA Methylation, Gene Silencing, Receptors, G-Protein-Coupled, HCT116 Cells, Mice

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