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Open Full Page DNA Methylation Represses IFN-;–Induced and Signal Transducer and Activator of Transcription 1–Mediated IFN Regulatory Factor 8 Activation in Colon Carcinoma Cells Jon M. McGough,1 Dafeng Yang,1 Shuang Huang,1 David Georgi,2 Stephen M. Hewitt,3 Christoph Ro¨cken,4 Marc Ta¨nzer,5 Matthias P.A. Ebert,5 and Kebin Liu1 Departments of 1Biochemistry and Molecular Biology and 2Pathology, Medical College of Georgia, Augusta, Georgia; 3Tissue Array Research Program, National Cancer Institute, NIH, Bethesda, Maryland; 4Institute of Pathology, Charite, Universita¨tsmedizin, Berlin, Germany; and 5Department of Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany Abstract IFN-;–activated IRF8 expression through IFN regulatory factor 8 (IRF8) is both constitutively MBD1-dependent and PIAS1-mediated inhibition of expressed and IFN-; inducible in hematopoietic and pSTAT1 function at the methylated IRF8 promoter. nonhematopoietic cells. We have shown that IRF8 (Mol Cancer Res 2008;6(12):1841–51) expression is silenced by DNA methylation in human colon carcinoma cells, but the molecular mechanism Introduction underlying methylation-dependent IRF8 silencing IFN regulatory factor 8 (IRF8) is a central mediator in remains elusive. In this study, we observed that IRF8 the IFN-g/signal transducer and activator of transcription 1 protein level is inversely correlated with the methylation (STAT1) signaling pathway and functions as a suppressor of status of the IRF8 promoter and the metastatic both hematopoietic and nonhematopoietic tumors (1-4). One of phenotype in human colorectal carcinoma specimens the prominent phenotypes of IRF8 null mice is marked clonal in vivo . Demethylation treatment or knocking down expansion of undifferentiated granulocytes and macrophages. DNMT1 and DNMT3b expression rendered the tumor These IRF8-deficient myeloid cells frequently progress to a ; cells responsive to IFN- to activate IRF8 transcription syndrome similar to human chronic myelogenous leukemia (2, in vitro . Bisulfite genomic DNA sequencing revealed that 5, 6). In human patients with chronic myelogenous leukemia the entire CpG island of the IRF8 promoter is methylated. and acute myeloid leukemia, IRF8 expression is dramatically Electrophoresis mobility shift assay revealed that DNA decreased (7). These studies thus revealed that IRF8 functions ; methylation does not directly inhibit IFN- –activated as a tumor suppressor of certain hematopoietic malignancies. phosphorylated signal transducer and activator of In an earlier study to identify differentially expressed genes ; transcription 1 (pSTAT1) binding to the IFN- activation between primary and metastatic colon carcinoma tumor cell in vitro site element in the IRF8 promoter . Chromatin lines using DNAmicroarray analysis, we identified that IFN- g immunoprecipitation assay revealed that pSTAT1 is induces IRF8 expression in human colon carcinoma cells (i.e., ; associated with the IFN- activation site element of the nonhematopoietic tumor cells) and that IRF8 expression level in vivo IRF8 promoter regardless of the methylation is inversely correlated with the metastatic phenotype (8). status of the IRF8 promoter. However, DNA methylation Recently, we showed that IRF8 can be repressed by DNA results in preferential association of PIAS1, a potent methylation in human colon carcinoma cells. We further inhibitor of pSTAT1, with pSTAT1 in the methylated showed that disruption of IRF8 function or silencing IRF8 IRF8 promoter region. Silencing methyl-CpG binding expression significantly decreased the tumor cell sensitivity to domain protein 1 (MBD1) expression resulted in IRF8 apoptosis and conferred the low metastatic tumor cells with ; activation by IFN- in human colon carcinoma cells metastatic potential in an experimental metastasis mouse model with methylated IRF8 promoter. Our data thus (3, 4, 9). The direct effect of IRF8 on nonhematopoietic tumor suggest that human colon carcinoma cells silence development has also been shown in various carcinoma cells (10, 11). It was shown that both constitutively expressed and IFN-g–induced IRF8 mediates apoptosis in lens carcinoma Received 6/13/08; revised 8/21/08; accepted 8/31/08. cells, and ectopic expression of IRF8 inhibited the clono- Grant support: CA133085 (K. Liu) from the National Cancer Institute, NIH. genicity of colon, lens, esophageal, and nasopharyngeal carci- M.P.A. Ebert is supported by the Else Kro¨ner-Fresenius-Stiftung (Homburg, noma cells (10, 11). Furthermore, a recent study has extended Germany). The costs of publication of this article were defrayed in part by the payment of the IRF8 promoter methylation to multiple human carcinomas, page charges. This article must therefore be hereby marked advertisement in including nasopharyngeal, cervical, breast, and esophageal accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Kebin Liu, Department of Biochemistry and Molecular carcinoma (11). Therefore, IRF8 also functions as an apoptosis Biology, Medical College of Georgia, 1459 Laney Walker Boulevard, regulator and tumor suppressor in nonhematopoietic tumors and Augusta, GA 30912. Phone: 706-721-9483; Fax: 706-721-6608. E-mail: its expression is regulated by DNAmethylation. In addition, [email protected] Copyright D 2008 American Association for Cancer Research. analysis of expressed sequence tag data in the UniGene doi:10.1158/1541-7786.MCR-08-0280 database of the National Center for Biotechnology Information Mol Cancer Res 2008;6(12). December 2008 1841 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2008 American Association for Cancer Research. 1842 McGough et al. indicates that IRF8 is expressed in a broad spectrum of IRF8 protein is only present in the nucleus (data not shown). human tumors, including bone, colorectal, gastrointestinal, Moreover, although IRF8 protein was detected in both nucleus glial, kidney, respiratory tract, muscle tissue, and uterine and cytoplasm of the colon carcinoma cells, IRF8-specific tumors. Examination of DNAmicroarray data deposited in staining was only observed in the nuclei of lymphocytes the National Center for Biotechnology Information Gene in the tumor-bearing lymph node (Fig. 1A, b1-b3). IRF8 is a Expression Omnibus database revealed that IRF8 expression transcription factor and is located in the nuclei of lymphocytes, is detected in human breast, bone, soft tissue, cervix, colorectal, and the nature of the cytoplasmic IRF8 staining in human glial, kidney, lung, skin, ovarian, and prostate cancers. Thus, colon carcinoma cells remains to be determined. IRF8 protein IRF8 is ubiquitously expressed in human tumors of diverse was not uniformly expressed in all tumor cells in the primary types and histologies. tumors; rather, IRF8-positive tumor cells are scattered in the Although IRF8 is constitutively expressed in macrophages, tumor tissue. other myeloid cells, B cells, and T cells, expression of IRF8 can To extend the above findings to a larger pool of human be dramatically up-regulated by IFN-g (12). The relative roles colorectal cancer specimens, we analyzed IRF8 protein levels in of constitutively expressed IRF8 and IFN-g–activated IRF8 are human colorectal carcinomas printed on tissue microarray. still not well defined and remain an active research area (12). Among the 37 primary colorectal carcinoma tissues interpret- IRF8 is also constitutively expressed in certain nonhemato- able, 31 (84%) exhibited IRF8 protein staining in the nucleus poietic tumor cells, albeit at lower level, but its expression can (Fig. 1B, a). We also separately analyzed liver metastases also be dramatically up-regulated by IFN-g (3, 8, 10) through derived from seven colorectal cancer patients. IRF8 protein was the IFN-gR–mediated signaling pathway (13). Binding of IFN-g not detected in the nucleus of the tumor cells in five of the to IFN-gR, which is ubiquitously but not uniformly expressed seven specimens (Fig. 1B, b). However, IRF8 protein was on all human nucleated cells (14), leads to transphosphorylation detected in the nucleus of the tumor cells in two of the seven of IFN-gR–associated Janus-activated kinase kinases followed (29%) liver metastases specimens (data not shown). Taken by phosphorylation and dimerization of cytosolic STAT1. The together, nuclear IRF8 protein is present in 81% (35 of 43) of phosphorylated STAT1 (pSTAT1) is translocated to the nucleus primary colorectal carcinoma specimens and in 23% (3 of 13) as an active transcription factor (15-17) and binds to the IFN-g of metastatic tumor specimens derived from colorectal cancer activation site (GAS) element to activate transcription of the patients, respectively. primary IFN-g response genes (13, 18). Our previous studies showed that human colon carcinoma cells silence IRF8 The IRF8 Promoter Region Is Frequently Methylated in expression through the IRF8 promoter DNAmethylation (3). Human Colorectal Carcinoma In vivo However, the molecular mechanisms underlying methylation- To determine whether the IRF8 promoter is hypermethylated dependent inhibition of IRF8 activation by IFN-g are unclear. in human colorectal carcinoma under physiologic conditions, In the present studies, we carried out detailed analysis of the we isolated genomic DNAfrom 21 primary tumor specimens molecular interactions between the IRF8 promoter DNAand derived from 21 human colorectal cancer patients and liver IFN-g–activated pSTAT1 in human colon carcinoma cells. metastases specimens derived from another 12
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