Epigenetic silencing of the interferon regulatory factor ICSBP/IRF8 in human multiple myeloma

Tshuikina, Marina; Jernberg-Wiklund, Helena; Nilsson, Kenneth; Öberg, Fredrik

doi:10.1016/j.exphem.2008.08.001

Cited by 36 publications

(28 citation statements)

References 40 publications

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“…Consistent with that idea, a number of earlier studies have shown that IRFs are silenced by DNA methylation in human neoplasias. (23)(24)(25)37,38) Here, we found that DNA methylation of IRF4, IRF5, and ⁄ or IRF8 is a frequent event in gastric cancer cell lines and that treatment with a demethylating agent (DAC) restores induction of IRF5 by p53, p63, or p73 and induction of IRF8 by IFN-c, which confirms the role played by DNA methylation in silencing the genes. Moreover, when applied together, interferon and DAC acted synergistically to suppress cell growth.…”

Section: Discussionsupporting

confidence: 64%

DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae

Yamashita

Toyota²,

Suzuki³

et al. 2010

Cancer Science

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Interferon regulatory factors (IRFs) are transcription factors known to play key roles in innate and adaptive immune responses, cell growth, apoptosis, and development. Their function in tumorigenesis of gastric cancer remains to be determined, however. In the present study, therefore, we examined epigenetic inactivation of IRF1-9 in a panel of gastric cancer cell lines. We found that expression of IRF4, IRF5, and IRF8 was frequently suppressed in gastric cancer cell lines; that methylation of the three genes correlated with their silencing; and that treating the cells with the demethylating agent 5-aza-2¢-deoxycytidine (DAC) restored their expression. Expression of IRF5 in cancer cells was enhanced by the combination of DAC treatment and adenoviral vector-mediated expression of p53, p63, or p73. Interferon-c-induced expression of IRF8 was also enhanced by DAC. Moreover, treating gastric cancer cells with DAC enhanced the suppressive effects of interferon-a, interferon-b, and interferon-c on cell growth. Among a cohort of 455 gastric cancer and noncancerous gastric tissue samples, methylation of IRF4 was frequently observed in both gastric cancer specimens and noncancerous specimens of gastric mucosa from patients with multiple gastric cancers, which suggests IRF4 methylation could be a useful molecular marker for diagnosing recurrence of gastric cancers. Our findings indicate that epigenetic IRF inactivation plays a key role in tumorigenesis of gastric cancer, and that inhibition of DNA methylation may restore the antitumor activity of interferons through up-regulation of IRFs. (Cancer Sci 2010; 101: 1708-1716 G astric cancer arises through the accumulation of multiple genetic changes, including mutation of adenomatous polyposis coli (APC), K-ras, and p53.(1) But recent studies have also shown that epigenetic changes such as DNA methylation are also importantly involved in the gene silencing seen in cancer.(2) For instance, genes involved in regulation of the cell cycle and apoptosis are now known to be inactivated by DNA methylation. (3)(4)(5) In addition we previously showed that a number of genes involved in signal transduction are epigenetically silenced in cancer. The affected genes include secreted frizzled-related protein 1 (SFRP1), SFRP2, dickkopf 1 (DKK1), and DKK2, which are negative regulators of WNT signaling, (6,7) Ras association domain family member 2 (RASSF2), a negative regulator of Ras;(8) and 14-3-3r and deafness, autosomal dominant 5 (DFNA5), two transcriptional targets of p53.(9,10) Because DNA methylation is an epigenetic change, which does not affect gene sequences, the silenced genes can be reactivated by demethylation, making DNA methylation a useful target of cancer therapy. (11,12) DNA methylation could also be used as a molecular marker for cancer detection. For instance, methylation of genes such as SFRP2 and GATA binding protein-4 (GATA-4) has been detected in stool DNA from colorectal cancer patients. (13,14) In gastric cancer, infection by Helicobacter pylori (H. pylori) induces...

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Section: Discussionsupporting

confidence: 64%

DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae

Yamashita

Toyota²,

Suzuki³

et al. 2010

Cancer Science

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“…From unsupervised clustering of the 161 presentation myeloma samples, it was clear that several independent methylation profiles exist within multiple myeloma: a t(4;14) group, 2 separate t(11;14) groups, and 2 separate hyperdiploid groups. These findings are in contrast to other chromosomal abnormalities, such as del(1p32.1), gain 1q, del(13q), del(16q), del(17p), or del (22), which did not affect clustering of the samples. The most distinct of these methylation profiles belonged to the t(4;14) cytogenetic subgroup, which showed more frequent hypermethylation of genes compared with the other subgroups.…”

Section: Discussioncontrasting

confidence: 53%

“…Genomic instability is a characteristic feature of myeloma cells in which translocations involving the IGH locus and MMSET/ FGFR3, CCND1, CCND3, MAF, and MAFB occur, as well as numerous structural copy number alterations, including del(1p), del(6q), del(8p), del(13q), del(16q), del (22), and gain of 1q. [4][5][6] However, the mechanisms involved in the progression from MGUS to myeloma are incompletely understood as, although present at decreased frequencies, the genetic markers characteristic of myeloma such as immunoglobulin heavy (IGH) chain rearrangements, hyperdiploidy, and gains and losses of chromosomal regions are also present in MGUS.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13] With the exception of one recent study, 14 the epigenetic factors contributing to the pathogenesis of myeloma have been studied on a gene-by-gene basis and, with the use of methylation-specific PCR, several genes have been identified that are hypermethylated, including VHL, XAF1, IRF8, TP53, CDKN2A, CDKN2B, DAPK, SOCS1, CDH1, PTGS2, CCND2, and DCC. [15][16][17][18][19][20][21][22] Promoter hypermethylation of cyclin-dependent kinase inhibitor 2A (CDKN2A) and TGFBR2 have been shown to correlate with poor prognosis in myeloma patients, although the prognostic value of CDKN2A hypermethylation remains debatable. 16,23,24 In this study we used the Infinium array (Illumina) to analyze CpG island promoter methylation with normal PCs, MGUS, myeloma, and PCL samples to identify methylation changes that may contribute to the pathogenesis of myeloma or that could act as prognostic factors.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma

Walker

Wardell

Chiecchio

et al. 2011

Blood

228

225

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We used genome-wide methylation microarrays to analyze differences in CpG methylation patterns in cells relevant to the pathogenesis of myeloma plasma cells (B cells, normal plasma cells, monoclonal gammopathy of undetermined significance [MGUS], presentation myeloma, and plasma cell leukemia). We show that methylation patterns in these cell types are capable of distinguishing nonmalignant from malignant cells and the main reason for this difference is hypomethylation of the genome at the transition from MGUS to presentation myeloma. In addition, gene-specific hypermethylation was evident at the myeloma stage. Differential methylation was also evident at the transition from myeloma to plasma cell leukemia with remethylation of the genome, particularly of genes involved in cell-cell signaling and cell adhesion, which may contribute to independence from the bone marrow microenvironment. There was a high degree of methylation variability within presentation myeloma samples, which was associated with cytogenetic differences between samples. More specifically, we found methylation subgroups were defined by translocations and hyperdiploidy, with t(4;14) myeloma having the greatest impact on DNA methylation. Two groups of hyperdiploid samples were identified, on the basis of unsupervised clustering, which had an impact on overall survival. Overall, DNA methylation changes significantly during disease progression and between cytogenetic subgroups. (Blood. 2011; 117(2):553-562)

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“…Regulation of IFNG and IRF genes by DNA methylation has been reported in several diseases, including BA, 5 and other conditions ranging from ulcerative colitis to various cancers. 22,28,29 The previous report of IFNG hypomethylation in BA focused on lymphocytes, but our studies suggest the possibility that these genes could be hypomethylated in the liver as well, consistent with our previous report showing decreased DNA methylation in cholangiocytes from BA patients. 4 Thus, our results here and elsewhere are consistent with a model in which decreased DNA methylation in cholangiocytes leads to aberrant activation of IFNG and other genes, resulting in biliary defects.…”

Section: Figsupporting

confidence: 81%

Interferon-Gamma Directly Mediates Developmental Biliary Defects

2013

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Biliary atresia (BA) is the most common identifiable hepatobiliary disease affecting infants, in which there are defects in intra-and extrahepatic bile ducts and progressive fibrosis. Activation of interferon-gamma (IFNc) appears to be critical in both patients with BA and in rodent models of BA. We have recently reported a zebrafish model of biliary disease that shares features with BA, in which inhibition of DNA methylation leads to intrahepatic biliary defects and activation of IFNc target genes. Here we report that ifng genes are hypomethylated and upregulated in zebrafish larvae treated with azacytidine (azaC), an inhibitor of DNA methylation. Injection of IFNc protein into developing zebrafish larvae leads to biliary defects, suggesting that activation of the IFNc pathway is sufficient to cause developmental biliary defects. These defects are associated with decreased cholangiocyte proliferation and with a decrease in the expression of vhnf1 (hnf1b, tcf2), which encodes a homeodomain protein with previously reported roles in biliary development in multiple models. These results support an importance of IFNc in mediating biliary defects, and also demonstrate the feasibility of direct injection of intact protein into developing zebrafish larvae.

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Epigenetic silencing of the interferon regulatory factor ICSBP/IRF8 in human multiple myeloma

Cited by 36 publications

References 40 publications

DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae

DNA methylation of interferon regulatory factors in gastric cancer and noncancerous gastric mucosae

Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma

Interferon-Gamma Directly Mediates Developmental Biliary Defects

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