Repression of IFN Regulatory Factor 8 by DNA Methylation Is a Molecular Determinant of Apoptotic Resistance and Metastatic Phenotype in Metastatic Tumor Cells

Yang, Dafeng; Thangaraju, Muthusamy; Greeneltch, Kristy M.; Browning, Darren D.; Schoenlein, Patricia V.; Tamura, Tomohide; Ozato, Keiko; Ganapathy, Vadivel; Abrams, Scott I.; Liu, Kebin

doi:10.1158/0008-5472.can-06-4068

Cited by 86 publications

(116 citation statements)

References 49 publications

(66 reference statements)

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“…This is consistent with earlier reports showing that IRF8 is silenced in colorectal cancer cell lines in a DNA methylation-dependent manner. (23) In contrast to the data obtained with cell lines, we did not find an increase in IRF8 methylation in primary gastric cancers, as compared to noncancerous tissues. This is in contrast to earlier studies showing that IRF8 is methylated in cancers of the colon, esophagus, and nasopharyngus.…”

Section: Discussioncontrasting

confidence: 99%

“…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: 66%

“…(23) These findings prompted us to speculate that epigenetic inactivation of IRF expression may play a key role in tumorigenesis.…”

mentioning

confidence: 99%

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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: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 66%

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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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“…[39][40][41] In AML, 7 out of 21 analyzed samples showed signs of promoter methylation. 42 However, high expression of IRF8 in the presence of methylated promoter has been reported for leukemic cell lines.…”

Section: Wt1 Expression Does Not Affect the Methylation Of The Irf8 Pmentioning

confidence: 99%

Wilms’ tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells

et al. 2010

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Wilms' tumor gene 1 (WT1) is a transcription factor involved in developmental processes. In adult hematopoiesis, only a small portion of early progenitor cells express WT1, whereas most leukemias show persistently high levels, suggesting an oncogenic role. We have previously characterized oncogenic BCR/ ABL1 tyrosine kinase signaling pathways for increased WT1 expression. In this study, we show that overexpression of BCR/ ABL1 in CD34 þ progenitor cells leads to reduced expression of interferon regulatory factor 8 (IRF8), in addition to increased WT1 expression. Interestingly, IRF8 is known as a tumor suppressor in some leukemias and we investigated whether WT1 might repress IRF8 expression. When analyzed in four leukemia mRNA expression data sets, WT1 and IRF8 were anticorrelated. Upon overexpression in CD34 þ progenitors, as well as in U937 cells, WT1 strongly downregulated IRF8 expression. All four major WT1 splice variants induced repression, but not the zinc-finger-deleted WT1 mutant, indicating dependence on DNA binding. A reporter construct with the IRF8 promoter was repressed by WT1, dependent on a putative WT1-response element. Binding of WT1 to the IRF8 promoter was demonstrated by chromatin immunoprecipitation. Our results identify IRF8 as a direct target gene for WT1 and provide a possible mechanism for oncogenic effects of WT1 in leukemia.

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“…In melanoma, for instance, one of the standard treatments is interferon, which induces tumor apoptosis, differentiation and increases the anti-tumor immune response. Silencing of genes involved in signaling downstream of interferon, such as interferon regulatory factor 8 and XIAPassociated factor 1 trigger resistance of tumor cells to interferon therapy (Reu et al, 2006;Yang et al, 2007). However, injection of decitabine in nude mice carrying melanoma xenografts led to resensitization to interferon treatment (Reu et al, 2006).…”

Section: Epigenetic Cancer Therapymentioning

confidence: 99%

Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy

2010

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An important feature of cancer is dysregulation of gene activity and gene expression, which is driven by a combination of acquired genetic and epigenetic alterations. Here, we will highlight how insights into the epigenetic processes underpinning tumor biology have led to the emerging field of cancer pharmaco-epigenomics. First, we will discuss how interference with the epigenetic machinery in cancer is leading to novel promising therapies, with several DNA methyltransferase and histone deacetylase inhibitors being approved for cancer treatment. Second, we will discuss how epigenetic markers in cancer may increasingly be used as complementary diagnostic tools, prognostic markers of disease progression, and predictive markers of treatment response. Although the anti-tumoral activities of epigenetic therapies have thus far been attributed to reactivation of silenced tumor-suppressor and/or apoptotic genes, they may also influence the tumor environment by directly affecting stromal cells. As an example, we will discuss how tumor-endothelial cells are regulated at the epigenetic level and are affected by methyltransferase and histone deacetylase inhibitors.

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Repression of IFN Regulatory Factor 8 by DNA Methylation Is a Molecular Determinant of Apoptotic Resistance and Metastatic Phenotype in Metastatic Tumor Cells

Cited by 86 publications

References 49 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

Wilms’ tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells

Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy

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