IFNγ Induces DNA Methylation-Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer.
Short-chain fatty acids, metabolites produced by colonic microbiota from fermentation of dietary fiber, act as anti-inflammatory agents in the intestinal tract to suppress proinflammatory diseases. GPR109A is the receptor for short-chain fatty acids. The functions of GPR109A have been the subject of extensive studies; however, the molecular mechanisms underlying GPR109A expression is largely unknown. We show that GPR109A is highly expressed in normal human colon tissues, but is silenced in human colon carcinoma cells. The GPR109A promoter DNA is methylated in human colon carcinoma. Strikingly, we observed that IFNγ, a cytokine secreted by activated T cells, activates GPR109A transcription without altering its promoter DNA methylation. Colon carcinoma grows significantly faster in IFNγ-deficient mice than in wild-type mice in an orthotopic colon cancer mouse model. A positive correlation was observed between GPR109A protein level and tumor-infiltrating T cells in human colon carcinoma specimens, and IFNγ expression level is higher in human colon carcinoma tissues than in normal colon tissues. We further demonstrated that IFNγ rapidly activates pSTAT1 that binds to the promoter of p300 to activate its transcription. p300 then binds to the GPR109A promoter to induce H3K18 hyperacetylation, resulting in chromatin remodeling in the methylated GPR109A promoter. The IFNγ-activated pSTAT1 then directly binds to the methylated but hyperacetylated GPR109 promoter to activate its transcription. Overall, our data indicate that GPR109A acts as a tumor suppressor in colon cancer, and the host immune system might use IFNγ to counteract DNA methylation-mediated GPR109A silencing as a mechanism to suppress tumor development.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
Kankana
K
Bardhan
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. Cancer Center, Georgia Regents University, Augusta, Georgia. Charlie Norwood VA Medical Center, Augusta, Georgia.
Amy V
AV
Paschall
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. Charlie Norwood VA Medical Center, Augusta, Georgia.
Dafeng
D
Yang
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
May R
MR
Chen
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. Cancer Center, Georgia Regents University, Augusta, Georgia. Charlie Norwood VA Medical Center, Augusta, Georgia.
Priscilla S
PS
Simon
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
Yangzom D
YD
Bhutia
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
Pamela M
PM
Martin
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. Cancer Center, Georgia Regents University, Augusta, Georgia.
Muthusamy
M
Thangaraju
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. Cancer Center, Georgia Regents University, Augusta, Georgia.
Darren D
DD
Browning
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. Cancer Center, Georgia Regents University, Augusta, Georgia.
Vadivel
V
Ganapathy
Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
Christopher M
CM
Heaton
University Hospital, Augusta, Georgia.
Keni
K
Gu
Charlie Norwood VA Medical Center, Augusta, Georgia. Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
Jeffrey R
JR
Lee
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. Cancer Center, Georgia Regents University, Augusta, Georgia. Charlie Norwood VA Medical Center, Augusta, Georgia. Kliu@gru.edu.
Kebin
K
Liu
D000107:Acetylation; D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*
C530636:HCAR2 protein, human; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D007371:Interferon-gamma; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human