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  • Oncogenomics
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Epigenetic disruption of interferon-γ response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas

Oncogene volume 27, pages 5267–5276 (2008)Cite this article

Abstract

16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT–PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100% in NPC, 88% in esophageal and 18–78% in other carcinoma cell lines) and in a large collection of primary carcinomas (78% in NPC, 36–71% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-γ stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas.

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Acknowledgements

This project was supported by a Michael and Betty Kadoorie Cancer Genetics Research Program (MBKCGRP) Grant to QT and a Hong Kong RGC Central Allocation Grant (CA06/07.SC03, QT). We thank Drs Bert Vogelstein, George Tsao (Dolly Huang), Sun Young Rha and Kaitai Yao for some cell lines, DSMZ (German Collection of Microorganisms and Cell Cultures) for the KYSE cell lines [Shimada et al., Cancer 69: 277–284 (1992)], Dr C Langford at the Wellcome Trust Sanger Institute, Cambridge, UK for aCGH slides, and Tzer-Jing Seng (Johns Hopkins Singapore) for her valuable help in aCGH analysis.

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Author notes

  1. K Y Lee and H Geng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Oncology, Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China

    K Y Lee, H Geng, K M Ng, A H Y Wong, X Wang, J Ying, A T C Chan & Q Tao

  2. Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China

    J Yu & J J Y Sung

  3. Department of Surgery, Chinese University of Hong Kong, Hong Kong, China

    A van Hasselt

  4. Hunan Yale (Xiang Ya) School of Medicine, Central South University, Changsha, China

    Y Cao

  5. State Key Laboratory in Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

    Y-X Zeng

  6. Department of Pathology, University of Hong Kong, Hong Kong, China

    G Srivastava

  7. Department of Biology, Hong Kong University of Science and Technology, Hong Kong, China

    M L Lung

  8. Henan Key Laboratory for Esophageal Cancer, Zhengzhou University College of Medicine and Cancer Research Center of Xinxiang Medical College, Henan, China

    L-D Wang

  9. Department of Biochemistry, Chinese University of Hong Kong, Hong Kong, China

    T T Kwok

  10. Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel

    B-Z Levi

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Correspondence to Q Tao.

Additional information

Note added in proof:

During the final preparation of this paper, Yang et al. reported IRF8 methylation in a single colon cell line (SW620), which is related to apoptotic resistance and tumor metastasis (Yang et al., Cancer Res. 2007; 67: 3301–3309).

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Lee, K., Geng, H., Ng, K. et al. Epigenetic disruption of interferon-γ response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas. Oncogene 27, 5267–5276 (2008). https://doi.org/10.1038/onc.2008.147

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