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Epigenetic Disruption of Interferon-Γ Response Through Silencing The Oncogene (2008) 27, 5267–5276 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ONCOGENOMICS Epigenetic disruption of interferon-c response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas KY Lee1,11, H Geng1,11,KMNg1,JYu2, A van Hasselt3, Y Cao4, Y-X Zeng5, AHY Wong1, X Wang1, J Ying1, G Srivastava6, ML Lung7, L-D Wang8, TT Kwok9, B-Z Levi10, ATC Chan1, JJY Sung2 and Q Tao1 1Cancer Epigenetics Laboratory, State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China; 2Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; 3Department of Surgery, Chinese University of Hong Kong, Hong Kong, China; 4Hunan Yale (Xiang Ya) School of Medicine, Central South University, Changsha, China; 5State Key Laboratory in Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; 6Department of Pathology, University of Hong Kong, Hong Kong, China; 7Department of Biology, Hong Kong University of Science and Technology, Hong Kong, China; 8Henan Key Laboratory for Esophageal Cancer, Zhengzhou University College of Medicine and Cancer Research Center of Xinxiang Medical College, Henan, China; 9Department of Biochemistry, Chinese University of Hong Kong, Hong Kong, China and 10Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel 16q24 is frequently deleted in multiple tumors including frequently silenced by epigenetic mechanism in multiple cancers of nasopharynx, esophagus, breast, prostate and carcinomas. liver. By array comparative genomic hybridization Oncogene (2008) 27, 5267–5276; doi:10.1038/onc.2008.147; (aCGH), we refined a 16q24 hemizygous deletion in published online 12 May 2008 nasopharyngeal carcinoma (NPC) cell lines. Semi-quanti- tative RT–PCR analysis revealed interferon regulatory Keywords: IRF8; methylation; CpG island; tumor factor 8 (IRF8) as the only downregulated gene within this suppressor gene; carcinoma 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 Introduction tissues, transcriptional silencing and promoter methyla- tion of IRF8 were frequently detected in multiple Carcinogenesis is a multistep process with the accumu- carcinoma (except for hepatocellular) cell lines (100% lation of multiple genetic and epigenetic changes (Jones in NPC, 88% in esophageal and 18–78% in other and Baylin, 2002). In addition to the contribution of carcinoma cell lines) and in a large collection of oncogenes, inactivation of tumor suppressor genes primary carcinomas (78% in NPC, 36–71% in other (TSGs) is also frequently involved (Jones and Baylin, carcinomas). Methylation of the IRF8 promoter led to the 2002; Baylin and Ohm, 2006). Genetic mutations disruption of its response to IFN-c stimulation. Pharma- including deletions disrupt TSG functions (Knudson, cological and genetic demethylation could restore IRF8 2001), whereas epigenetic silencing also inactivates expression, indicating a direct epigenetic mechanism. TSGs through methylation of promoter CpG islands Ectopic expression of IRF8 in tumor cells lacking its (CGIs), which is a characteristic epigenetic feature of ONCOGENOMICS expression strongly inhibited their clonogenicity, confirm- tumor DNA (Jones and Baylin, 2002). ing its tumor suppressor function. Thus, IRF8 was Nasopharyngeal carcinoma (NPC) is prevalent in identified as a functional tumor suppressor, which is Southern China and Southeast Asia (Tao and Chan, 2007). Although its pathogenesis has been shown to be strongly associated with Epstein–Barr virus, its mole- Correspondence: Professor Q Tao, Cancer Epigenetics Laboratory, cular mechanism is still poorly elucidated (Lo et al., Department of Clinical Oncology, Sir YK Pao Center for Cancer, 2004; Tao and Chan, 2007). Numerous genetic altera- Prince of Wales Hospital, Chinese University of Hong Kong, tions have been detected in NPC cell lines and tumors, Hong Kong, China. including 3p14–22, 11q13.3–24, 13q14.3–22, 14q24.3–32.1 E-mail: [email protected] and 16q21–24 (Chen et al., 1999; Lo et al., 2000; 11These authors contributed equally to this work. Received 7 November 2007; revised 21 March 2008; accepted 1 April Tao and Chan, 2007). These regions thus represent 2008; published online 12 May 2008 the critical TSG loci for NPC. Previous searches for Methylation of IRF8 in multiple carcinomas KY Lee et al 5268 putative TSGs in these regions have identified only few clone to locus 16q24.1, spanning B160-kb, with three candidates, with tumor-specific promoter methylation, genes, COX4NB, COX4I1 and IRF8 residing at this such as BLU and RASSF1A at 3p21 (Lo et al., 2001; locus (Figure 1a). Semi-quantitative RT–PCR analysis Qiu et al., 2004), CADM1/TSLC1 at 11q23.1 (Lung revealed IRF8 silencing in 5 of 6 NPC cell lines with et al., 2006); THY1/CD90 at 11q22.3 (Lung et al., 2005), weak expression in C666-1, but not for the other two CDH1 at 16q22.1 (Chang et al., 2003), ADAMTS18 and genes COX4NB and COX4I1, suggesting that IRF8 is CDH13 at 16q23 (Sun et al., 2007; Jin et al., 2007b). the candidate TSG located at the 16q24.1 deletion These limited findings suggest that additional cancer- (Figure 1b). related genes are yet to be identified in NPC in the reported regions, or other unidentified loci. Frequent downregulation of IRF8 in multiple carcinomas In this study, we have refined a 16q24.1 deletion as We further determined IRF8 expression in a panel of one of the critical tumor suppressor loci in NPC cell normal adult and fetal tissues and multiple cell lines by lines using high-resolution, 1-Mb array comparative semi-quantitative RT–PCR. IRF8 expression was de- genomic hybridization (aCGH) analysis (Ying et al., tected in all normal tissues including nasopharynx and 2006). Loss of heterozygosity (LOH) at 16q24 is also esophagus (Figure 1d), as well as immortalized normal frequently present in multiple other solid tumors, such nasopharyngeal (NP69) and esophageal epithelial (NE1 as breast, prostate, hepatocellular and Wilm’s tumor and NE3) cell lines (Figure 2a). In contrast, IRF8 was (Lo et al., 2000; Paige et al., 2000; Jin et al., 2007b), frequently downregulated or silenced in carcinoma cell suggesting the presence of critical TSG(s) at this locus. lines of nasopharyngeal, esophageal, breast, lung, Several functional candidate TSGs have been identified cervical and colorectal carcinomas (Figure 2a), but less at this locus including CDH13 (Toyooka et al., 2001). frequently in gastric and seldom in hepatocellular Thus, it is needed to search thoroughly for more carcinoma cell lines (Supplementary Figure). Mean- TSGs at this locus and define their functions in while, expression of the IRF8 protein was confirmed by tumors. western blot in normal esophageal epithelial tissues and Among the genes resided at the 16q24.1 deletion, normal lymphoid cell line LCL-CCL256.1 (Figure 2b). silencing of interferon regulatory factor 8 (IRF8) was However, IRF8 was absent in HONE1 and HCT116 identified in several NPC cell lines. IRF8 is also known cell lines that are completely methylated and silenced for as interferon consensus sequence-binding protein this gene. (ICSBP), which belongs to the IRF family of transcrip- tion factors (Nguyen et al., 1997). IRF8 has been characterized as a central element of the interferon Methylation of the IRF8 promoter correlates (IFN)-g-signaling pathway, which modulates immune with its transcriptional silencing response and also regulates cell growth and differentia- We then examined the possible genetic/epigenetic tion (Tamura and Ozato, 2002). IRF8-deficient mice mechanisms of IRF8 downregulation. As predicted by developed a human chronic myelogenous leukemia online CpG Island Searcher (http://cpgislands.usc.edu/), (CML)-like disease (Holtschke et al., 1996). In patients there is a CGI spanning the transcription start site of with CML and acute myelogenous leukemia, IRF8 IRF8 (Figure 1c). Methylation-specific PCR (MSP) was expression was dramatically decreased, suggesting that thus performed to study the methylation status of this IRF8 could be a candidate TSG (Schmidt et al., 1998). CGI. Results showed that IRF8 was frequently methy- Here, we report the frequent epigenetic inactivation of lated in cell lines with downregulation (6 of 6 IRF8 in NPC, as well as other common carcinomas, nasopharyngeal, 14 of 16 esophageal, 7 of 9 breast, 3 such as esophageal, breast, cervical, lung and colorectal of 4 colorectal, 5 of 7 lung, 4 of 6 cervical and 3 of 17 carcinomas. Methylation of the IRF8 promoter gastric carcinoma cell lines) (Figure 2a, Supplementary abolishes its response to IFN-g. Moreover, ectopic Figure, Table 1), whereas no methylation was detected expression of IRF8 in silenced tumor cells strongly in the immortalized epithelial cell lines (NP69, NE1 and inhibited their clonogenicity, indicating that IRF8 is a NE3), indicating that methylation is tumor specific functional TSG. (Figure 2a). The presence of either unmethylated or methylated promoter alleles in virtually all cell lines including silenced ones
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