Non-promoter DNA hypermethylation of Zygote Arrest 1 (ZAR1) in neuroblastomas

Sugito, Kiminobu; Kawashima, Hiroyuki; Yoshizawa, Shinsuke; Uekusa, Shota; Hoshi, Reina; Furuya, Takeshi; Kaneda, Hide; Hosoda, Toshifumi; Konuma, Noriyoshi; Masuko, Takayuki; Ohashi, Keiji; Ikeda, Taro; Koshinaga, Tsugumichi; Tomita, Ryouichi; Shinojima, Yui; Fujiwara, Kyoko; Watanabe, Takao; Held, William A.; Nagase, Hiroki

doi:10.1016/j.jpedsurg.2012.08.008

Cited by 11 publications

(7 citation statements)

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“…In another study, promoter hypermethylation and its negative correlation with the gene expression was demonstrated for genes TMEM106A and SCGB3A1 [47]. The gene ZAR1 from UPUP-only group has been reported to be hypermethylated and upregulated in neuroblastoma, while CPT1B was upregulated in PCa and breast cancer, in which the gene promotes chemo-resistance [48,49]. Another interesting gene from the UPUP-only group is GSC (Goosecoid), for which the upregulated expression has been associated with phenotype-specific DNA methylation downstream of the TSS in a PCa mouse model [50].…”

Section: Discussionmentioning

confidence: 94%

DNA hypermethylation associated with upregulated gene expression in prostate cancer demonstrates the diversity of epigenetic regulation

2020

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Background: Prostate cancer (PCa) has the highest incidence rates of cancers in men in western countries. Unlike several other types of cancer, PCa has few genetic drivers, which has led researchers to look for additional epigenetic and transcriptomic contributors to PCa development and progression. Especially datasets on DNA methylation, the most commonly studied epigenetic marker, have recently been measured and analysed in several PCa patient cohorts. DNA methylation is most commonly associated with downregulation of gene expression. However, positive associations of DNA methylation to gene expression have also been reported, suggesting a more diverse mechanism of epigenetic regulation. Such additional complexity could have important implications for understanding prostate cancer development but has not been studied at a genome-wide scale. Results: In this study, we have compared three sets of genome-wide single-site DNA methylation data from 870 PCa and normal tissue samples with multi-cohort gene expression data from 1117 samples, including 532 samples where DNA methylation and gene expression have been measured on the exact same samples. Genes were classified according to their corresponding methylation and expression profiles. A large group of hypermethylated genes was robustly associated with increased gene expression (UPUP group) in all three methylation datasets. These genes demonstrated distinct patterns of correlation between DNA methylation and gene expression compared to the genes showing the canonical negative association between methylation and expression (UPDOWN group). This indicates a more diversified role of DNA methylation in regulating gene expression than previously appreciated. Moreover, UPUP and UPDOWN genes were associated with different compartments-UPUP genes were related to the structures in nucleus, while UPDOWN genes were linked to extracellular features. Conclusion: We identified a robust association between hypermethylation and upregulation of gene expression when comparing samples from prostate cancer and normal tissue. These results challenge the classical view where DNA methylation is always associated with suppression of gene expression, which underlines the importance of considering corresponding expression data when assessing the downstream regulatory effect of DNA methylation.

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Section: Discussionmentioning

confidence: 94%

DNA hypermethylation associated with upregulated gene expression in prostate cancer demonstrates the diversity of epigenetic regulation

2020

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“…In malignant melanoma, ZAR1 was intra-genically methylated (exon 1) and ZAR1 was overexpressed in some hypermethylated melanoma cell lines [15]. Non-promoter hypermethylation was found in brain tumours and neuroblastoma [16, 17]. Expression of ZAR1 was absent in hypermethylated glioma cell lines [16], but ZAR1 was detected in hypermethylated neuroblastoma [17].…”

Section: Introductionmentioning

confidence: 99%

“…Non-promoter hypermethylation was found in brain tumours and neuroblastoma [16, 17]. Expression of ZAR1 was absent in hypermethylated glioma cell lines [16], but ZAR1 was detected in hypermethylated neuroblastoma [17]. It was proposed that methylation-related aberrant ZAR1 expression was unlikely to be related to glioma tumorigenesis [16].…”

Section: Introductionmentioning

confidence: 99%

ZAR1 is a novel epigenetically inactivated tumour suppressor in lung cancer

et al. 2017

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BackgroundLung cancer is the leading cause of cancer-related deaths with 1.8 million new cases each year and poor 5-year prognosis. Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby can promote cancer development and progression.ResultsIn this study, we analysed ZAR1 (zygote arrest 1), which has been said to be a maternal-effect gene and its expression mostly limited to certain reproductive tissues. Our study shows that ZAR1 is expressed in normal lung but inactivated by promoter methylation in lung cancer. ZAR1 is hypermethylated in primary lung cancer samples (22% small cell lung carcinoma (SCLC) and 76% non-small cell lung carcinoma (NSCLC), p < 0.001) vs. normal control lung tissue (11%). In lung cancer cell lines, ZAR1 was significantly methylated in 75% of SCLC and 83% of NSCLC vs. normal tissue (p < 0.005/0.05). In matching tumours and control tissues, we observed that NSCLC primary tumour samples exhibited a tumour-specific promoter methylation of ZAR1 in comparison to the normal control lung tissue. Demethylation treatment of various lung cancer cell lines reversed ZAR1 promoter hypermethylation and subsequently re-established ZAR1 expression. In addition, we could show the growth inhibitory potential of ZAR1 in lung cancer cell lines and cancer cell lines. Exogenous expression of ZAR1 not only inhibited colony formation but also blocked cell cycle progression of cancer cell lines.ConclusionsOur study shows for the first time the lung tumour-specific epigenetic inactivation of ZAR1 due to DNA methylation of its CpG island promoter. Furthermore, ZAR1 was characterised by the ability to block tumour growth through the inhibition of cell cycle progression in cancer cell lines. We propose that ZAR1 could serve as an epigenetically inactivated biomarker in lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0360-4) contains supplementary material, which is available to authorized users.

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“…In the human embryo, both maternal and paternal zygote gene activation (ZGA) at the 4–8 cell stage is implemented through MEG -dominated alterations of the CpG histone methylation status by gene-encoded methyltransferase/demethylases ( DNMT/DM ) ( 20 , 21 ). MEGs operate in zygotic reprograming through numerous maternal factors including cis-acting ZAR1, 2 (zygote arrest)/ZAR-like (ZARL) proteins in translational control sequences (TCS) that bind to maternal mRNAs at 3′UTR ( 22 ). Mutant ZAR1 arrests late 2-cell-stage zygotes through abnormal methylation of histones H3K4/H3K9 (histone H3 lysine4/9) and downregulate chromatin-modifying genes Dppa (maternal factor Stella, peri-plasmic polypeptide haloalkane dehydrogenase) and Piwil2 (protein of the ARGONAUTE family) ( 23 ).…”

Section: Gene Translation In Cancer Etiologymentioning

confidence: 99%

Potential Gene Interactions in the Cell Cycles of Gametes, Zygotes, Embryonic Stem Cells and the Development of Cancer

Prindull

2015

Front. Oncol.

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ObjectivesThis review is to explore whether potential gene interactions in the cell cycles of gametes, zygotes, and embryonic stem (ES) cells are associated with the development of cancer.MethodsMEDPILOT at the Central Library of the University of Cologne, Germany (Zentralbibliothek Köln) that covers 5,800 international medical journals and 4,300 E-journals was used to collect data. The initial searches were done in December 2012 and additional searches in October 2013–May 2015. The search terms included “cancer development,” “gene interaction,” and “ES cells,” and the time period was between 1998 and 2015. A total of 147 articles in English language only were included in this review.ResultsTransgenerational gene translation is implemented in the zygote through interactions of epigenetic isoforms of transcription factors (TFs) from parental gametes, predominantly during the first two zygote cleavages. Pluripotent transcription factors may provide interacting links with mutated genes during zygote-to-ES cell switches. Translation of post-transcriptional carcinogenic genes is implemented by abnormally spliced, tumor-specific isoforms of gene-encoded mRNA/non-coding RNA variants of TFs employing de novo gene synthesis and neofunctionalization. Post-translationally, mutated genes are preserved in pre-neoplastic ES cell subpopulations that can give rise to overt cancer stem cells. Thus, TFs operate as cell/disease-specific epigenetic messengers triggering clinical expression of neoplasms.ConclusionPotential gene interactions in the cell cycle of gametes, zygotes, and ES cells may play some roles in the development of cancer.

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Non-promoter DNA hypermethylation of Zygote Arrest 1 (ZAR1) in neuroblastomas

Cited by 11 publications

References 14 publications

DNA hypermethylation associated with upregulated gene expression in prostate cancer demonstrates the diversity of epigenetic regulation

DNA hypermethylation associated with upregulated gene expression in prostate cancer demonstrates the diversity of epigenetic regulation

ZAR1 is a novel epigenetically inactivated tumour suppressor in lung cancer

Potential Gene Interactions in the Cell Cycles of Gametes, Zygotes, Embryonic Stem Cells and the Development of Cancer

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