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Molecular and Cellular Biology, November 2007, p. 7886-7894, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.01547-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Epigenetic Control of the Immune Escape Mechanisms in Malignant Carcinomas{triangledown}

A. Francesca Setiadi,1,2,3 Muriel D. David,1 Robyn P. Seipp,1,2,3 Jennifer A. Hartikainen,1,2,5 Rayshad Gopaul,2 and Wilfred A. Jefferies1,2,3,4,5*

Biomedical Research Centre, Vancouver, British Columbia V6T 1Z3, Canada,1 Michael Smith Laboratories, Vancouver, British Columbia V6T 1Z4, Canada,2 Department of Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada,3 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada,4 Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada5

Received 23 August 2007/ Accepted 30 August 2007

Downregulation of the transporter associated with antigen processing 1 (TAP-1) has been observed in many tumors and is closely associated with tumor immunoevasion mechanisms, growth, and metastatic ability. The molecular mechanisms underlying the relatively low level of transcription of the tap-1 gene in cancer cells are largely unexplained. In this study, we tested the hypothesis that epigenetic regulation plays a fundamental role in controlling tumor antigen processing and immune escape mechanisms. We found that the lack of TAP-1 transcription in TAP-deficient cells correlated with low levels of recruitment of the histone acetyltransferase, CBP, to the TAP-1 promoter. This results in lower levels of histone H3 acetylation at the TAP-1 promoter, leading to a decrease in accessibility of the RNA polymerase II complex to the TAP-1 promoter. These observations suggest that CBP-mediated histone H3 acetylation normally relaxes the chromatin structure around the TAP-1 promoter region, allowing transcription. In addition, we found a hitherto-unknown mechanism wherein interferon gamma up-regulates TAP-1 expression by increasing histone H3 acetylation at the TAP-1 promoter locus. These findings lie at the heart of understanding immune escape mechanisms in tumors and suggest that the reversal of epigenetic codes may provide novel immunotherapeutic paradigms for intervention in cancer.

* Corresponding author. Mailing address: Biomedical Research Centre, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Phone: (604) 822-6961. Fax: (604) 822-6780. E-mail: wilf{at}brc.ubc.ca

{triangledown} Published ahead of print on 17 September 2007.

Molecular and Cellular Biology, November 2007, p. 7886-7894, Vol. 27, No. 22
0270-7306/07/$08.00+0     doi:10.1128/MCB.01547-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Setiadi, A. F., Omilusik, K., David, M. D., Seipp, R. P., Hartikainen, J., Gopaul, R., Choi, K. B., Jefferies, W. A. (2008). Epigenetic Enhancement of Antigen Processing and Presentation Promotes Immune Recognition of Tumors. Cancer Res. 68: 9601-9607 [Abstract] [Full Text]  


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