Epigenetic silencing of the imprinted geneZAC by DNA methylation is an early event in the progression of human ovarian cancer

Department of Molecular Genetics, Division of Molecular and Cell Therapeutics, Medical Institute of Bioregulation, Kyusyu University, Oita, Japan.
International Journal of Cancer (Impact Factor: 5.09). 07/2005; 115(5):690-700. DOI: 10.1002/ijc.20971
Source: PubMed


ZAC is a paternally expressed, imprinted gene located on chromosome 6q24, within a region known to harbor a tumor suppressor gene for several types of neoplasia, including human ovarian cancer (HOC). We have failed to identify genetic mutations in the ZAC gene in tumor material. Many imprinted genes contain differentially allele-specific-methylated regions (DMR) and harbor promoter activity that is regulated by the DNA methylation. Aberrant DNA methylation is a common feature of neoplasia and changes in DNA methylation at the ZAC locus have been reported in some cases of HOC. We investigated the DNA methylation and ZAC mRNA expression levels in a larger sample of primary HOC material, obtained by laser capture microdissection. ZAC mRNA expression was reduced in the majority of samples and this correlated with hypermethylation of the ZAC-DMR. Treatment of hypermethylated cells lines with a demethylating agent restored ZAC expression. Our studies indicate that transcriptional silencing of ZAC is likely to be caused by DNA methylation in HOC. Forced expression of ZAC resulted in a reduction in proliferation and marked induction of apoptotic cell death. The ZAC-mediated apoptosis signal is p53-independent and eliminated by inhibitors of caspase 3, 8 and 9. Reduced expression of ZAC would therefore favor tumor progression. As there were no significant differences in either DNA methylation or expression of ZAC mRNA between localized and advanced tumors, our data indicates that loss of ZAC is a relatively early event in HOC. (Supplementary material for this article can be found on the International Journal of Cancer website at

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    • "Indeed, such verification is difficult because imprinted genes can be regulated in specific cell types and developmental stages [5]. To overcome this limitation, we modified previously employed approaches to identify neuron-specific imprinted genes [10], [11]. Using this method in mice, we identified a novel neuronally imprinted gene, sorting nexin protein 14 (Snx14). "
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    ABSTRACT: Genomic imprinting describes an epigenetic process through which genes can be expressed in a parent-of-origin-specific manner. The monoallelic expression of imprinted genes renders them particularly susceptible to disease causing mutations. A large proportion of imprinted genes are expressed in the brain, but little is known about their functions. Indeed, it has proven difficult to identify cell type-specific imprinted genes due to the heterogeneity of cell types within the brain. Here we used laser capture microdissection of visual cortical neurons and found evidence that sorting nexin 14 (Snx14) is a neuronally imprinted gene in mice. SNX14 protein levels are high in the brain and progressively increase during neuronal development and maturation. Snx14 knockdown reduces intrinsic excitability and severely impairs both excitatory and inhibitory synaptic transmission. These data reveal a role for monoallelic Snx14 expression in maintaining normal neuronal excitability and synaptic transmission.
    PLoS ONE 05/2014; 9(5):e98383. DOI:10.1371/journal.pone.0098383 · 3.23 Impact Factor
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    • "Alterations in the expression of imprinted genes represent one of the most common changes seen in cancer [17,18]. Some imprinted genes, including H19[19], GTL2[20], PEG1, PEG3[21], LIT1 (KCNQ1OT1) [22] and ZAC[23] are known to act, or are strongly implicated to act, as tumor suppressor genes (TSGs). Furthermore, imprinted genes play key roles in regulating growth and differentiation [24]. "
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    ABSTRACT: Background hiPSCs are generated through epigenetic reprogramming of somatic tissue. Genomic imprinting is an epigenetic phenomenon through which monoallelic gene expression is regulated in a parent-of-origin-specific manner. Reprogramming relies on the successful erasure of marks of differentiation while maintaining those required for genomic imprinting. Loss of imprinting (LOI), which occurs in many types of malignant tumors, would hinder the clinical application of hiPSCs. Results We examined the imprinting status, expression levels and DNA methylation status of eight imprinted genes in five independently generated hiPSCs. We found a low frequency of LOI in some lines. Where LOI was identified in an early passage cell line, we found that this was maintained through subsequent passages of the cells. Just as normal imprints are maintained in long-term culture, this work suggests that abnormal imprints are also stable in culture. Conclusions Analysis of genomic imprints in hiPSCs is a necessary safety step in regenerative medicine, with relevance both to the differentiation potential of these stem cells and also their potential tumorigenic properties.
    BMC Genetics 04/2013; 14(1):32. DOI:10.1186/1471-2156-14-32 · 2.40 Impact Factor
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    • "ZAC is also a tumor supressor gene, with loss of expression associated with carcinogenesis in basal and squamous cell carcinomas, pituitary adenomas, and breast cancer (Basyuk et al. 2005; Bilanges et al. 1999; Koy et al. 2004; Pagotto et al. 2000). More specifi c to imprintome studies, epigenetic silencing of ZAC by hypermethylation has been observed in several cancer types, specifi cally as an early event in ovarian cancer (Kamikihara et al. 2005). Another imprinted central regulator of note is KLF14, which has robust monoalleleic maternal expression in all mouse and human embryonic tissues tested. "
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    ABSTRACT: Imprinted genes form a special subset of the genome, exhibiting monoallelic expression in a parent-of-origin–dependent fashion. This monoallelic expression is controlled by parental-specific epigenetic marks, which are established in gametogenesis and early embryonic development and are persistent in all somatic cells throughout life. We define this specific set of cis-acting epigenetic regulatory elements as the imprintome, a distinct and specially tasked subset of the epigenome. Imprintome elements contain DNA methylation and histone modifications that regulate monoallelic expression by affecting promoter accessibility, chromatin structure, and chromatin configuration. Understanding their regulation is critical because a significant proportion of human imprinted genes are implicated in complex diseases. Significant species variation in the repertoire of imprinted genes and their epigenetic regulation, however, will not allow model organisms solely to be used for this crucial purpose. Ultimately, only the human will suffice to accurately define the human imprintome.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 12/2012; 53(3-4):341-58. DOI:10.1093/ilar.53.3-4.341 · 2.39 Impact Factor
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