H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance.

Abstract

The Fas-FasL effector mechanism plays a key role in cancer immune surveillance by host T cells, but metastatic human colon carcinoma often uses silencing Fas expression as a mechanism of immune evasion. The molecular mechanism under FAS transcriptional silencing in human colon carcinoma is unknown. We performed genome-wide chromatin immunoprecipitation sequencing analysis and identified that the FAS promoter is enriched with H3K9me3 in metastatic human colon carcinoma cells. The H3K9me3 level in the FAS promoter region is significantly higher in metastatic than in primary cancer cells, and it is inversely correlated with Fas expression level. We discovered that verticillin A is a selective inhibitor of histone methyltransferases SUV39H1, SUV39H2, and G9a/GLP that exhibit redundant functions in H3K9 trimethylation and FAS transcriptional silencing. Genome-wide gene expression analysis identified FAS as one of the verticillin A target genes. Verticillin A treatment decreased H3K9me3 levels in the FAS promoter and restored Fas expression. Furthermore, verticillin A exhibited greater efficacy than decitabine and vorinostat in overcoming colon carcinoma resistance to FasL-induced apoptosis. Verticillin A also increased DR5 expression and overcame colon carcinoma resistance to DR5 agonist drozitumab-induced apoptosis. Interestingly, verticillin A overcame metastatic colon carcinoma resistance to 5-fluorouracil in vitro and in vivo. Using an orthotopic colon cancer mouse model, we demonstrated that tumor-infiltrating cytotoxic T lymphocytes are FasL(+) and that FasL-mediated cancer immune surveillance is essential for colon carcinoma growth control in vivo. Our findings determine that H3K9me3 of the FAS promoter is a dominant mechanism underlying FAS silencing and resultant colon carcinoma immune evasion and progression.

• Authors: Amy V Paschall, Dafeng Yang, Chunwan Lu, Jeong-Hyeon Choi, Xia Li, Feiyan Liu, Mario Figueroa, Nicholas H Oberlies, Cedric Pearce, Wendy B Bollag, Asha Nayak-Kapoor, Kebin Liu
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 4 Pg. 1868-82 (Aug 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26136424 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Fas Ligand Protein
• Histocompatibility Antigens
• Histones
• Indoles
• Repressor Proteins
• fas Receptor
• verticillins
• SUV39H1 protein, human
• Histone Methyltransferases
• Methyltransferases
• EHMT2 protein, human
• Histone-Lysine N-Methyltransferase
• SUV39H2 protein, human
• Fluorouracil

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, etiology, pathology)
• DNA Methylation
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Fas Ligand Protein (metabolism)
• Fluorouracil (pharmacology)
• Gene Expression Profiling
• Gene Silencing
• Genome-Wide Association Study
• Histocompatibility Antigens (metabolism)
• Histone Methyltransferases
• Histone-Lysine N-Methyltransferase (antagonists & inhibitors, metabolism)
• Histones (metabolism)
• Humans
• Indoles (pharmacology)
• Inhibitory Concentration 50
• Liver (drug effects, metabolism)
• Methylation (drug effects)
• Methyltransferases (metabolism)
• Mice
• Promoter Regions, Genetic
• Repressor Proteins (metabolism)
• Tumor Escape (genetics, immunology)
• Xenograft Model Antitumor Assays
• fas Receptor (genetics)