IFNγ Induces DNA Methylation–Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer
Autor: | Vadivel Ganapathy, Christopher M. Heaton, Yangzom D. Bhutia, Dafeng Yang, May R. Chen, Muthusamy Thangaraju, Keni Gu, Jeffrey R. Lee, Kankana Bardhan, Amy V. Paschall, Pamela M. Martin, Kebin Liu, Priscilla S. Simon, Darren D. Browning |
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Rok vydání: | 2015 |
Předmět: |
Cancer Research
Colorectal cancer medicine.medical_treatment Immunology Apoptosis Receptors Nicotinic Biology Article Chromatin remodeling Receptors G-Protein-Coupled Interferon-gamma Mice Transcription (biology) Cell Line Tumor medicine Animals Humans Gene silencing Genes Tumor Suppressor Mice Knockout Mice Inbred BALB C Carcinoma Acetylation Promoter Methylation DNA Methylation medicine.disease Molecular biology Disease Models Animal Cytokine Colonic Neoplasms DNA methylation E1A-Associated p300 Protein |
Zdroj: | Cancer Immunology Research. 3:795-805 |
ISSN: | 2326-6074 2326-6066 |
Popis: | 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. Cancer Immunol Res; 3(7); 795–805. ©2015 AACR. |
Databáze: | OpenAIRE |
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