Identification of Frequent Differentially Methylated Region in Sporadic Bladder Cancers

Hasegawa, Ryo; Fujiwara, Kyoko; Obinata, Daisuke; Kawashima, Hiroyuki; Shinojima, Yui; Igarashi, Jun; Wang, Xiaofei; Ghosh, Srimoyee; Nagase, Hiroki; Takahashi, Satoru

doi:10.1159/000365197

Cited by 8 publications

(6 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNA methylation is a significant epigenetic mechanism of gene regulation that can interpret the tumor genetic heterogeneity. Recent studies have demonstrated that hypomethylation of the CpG sites of ZAR1 gene was implicated in a high proportion of muscle-invasive bladder cancers [40]. …”

Section: Basis Of Tumor Heterogeneity: Genetic Heterogeneitymentioning

confidence: 99%

Bladder Tumor Heterogeneity: The Impact on Clinical Treatment

Chen¹,

Qi²,

Cao³

et al. 2015

Urol Int

View full text Add to dashboard Cite

Bladder cancer relapse and treatment failure in most patients have often been attributed to chemoresistance in tumor cells and metastasis. Emerging evidence indicates that tumor heterogeneity may play an equally important role and extends to virtually all measurable properties of cancer cells. Although the idea of tumor heterogeneity is not new, little attention has been paid to applying it to understand and control bladder cancer progression. With the development of biotechnology, such as Gene sequencing, recent advances in understanding its generation model, original basis, consequent problems, and derived therapies provide great potential for tumor heterogeneity to be considered a new insight in the treatment of bladder cancers.

show abstract

Section: Basis Of Tumor Heterogeneity: Genetic Heterogeneitymentioning

confidence: 99%

Bladder Tumor Heterogeneity: The Impact on Clinical Treatment

Chen¹,

Qi²,

Cao³

et al. 2015

Urol Int

View full text Add to dashboard Cite

show abstract

“…In hypermethylated neuroblastoma, however, expression of ZAR1 was detected and indicated that ZAR1 knockdown promotes differentiation in neuroblastoma cells [13]. Intragenic ZAR1 methylation decreased in high-grade vs. low-grade tumours of the bladder [14]. In hepatitis C virus, positive liver cancer ZAR1 was reported to be methylated in exon 1 [15].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic therapy of novel tumour suppressor ZAR1 and its cancer biomarker function

et al. 2019

View full text Add to dashboard Cite

BackgroundCancer still is one of the leading causes of death and its death toll is predicted to rise further. We identified earlier the potential tumour suppressor zygote arrest 1 (ZAR1) to play a role in lung carcinogenesis through its epigenetic inactivation.ResultsWe are the first to report that ZAR1 is epigenetically inactivated not only in lung cancer but also across cancer types, and ZAR1 methylation occurs across its complete CpG island. ZAR1 hypermethylation significantly correlates with its expression reduction in cancers. We are also the first to report that ZAR1 methylation and expression reduction are of clinical importance as a prognostic marker for lung cancer and kidney cancer. We further established that the carboxy (C)-terminally present zinc-finger of ZAR1 is relevant for its tumour suppression function and its protein partner binding associated with the mRNA/ribosomal network. Global gene expression profiling supported ZAR1's role in cell cycle arrest and p53 signalling pathway, and we could show that ZAR1 growth suppression was in part p53 dependent. Using the CRISPR-dCas9 tools, we were able to prove that epigenetic editing and reactivation of ZAR1 is possible in cancer cell lines.ConclusionZAR1 is a novel cancer biomarker for lung and kidney, which is epigenetically silenced in various cancers by DNA hypermethylation. ZAR1 exerts its tumour suppressive function in part through p53 and through its zinc-finger domain. Epigenetic therapy can reactivate the ZAR1 tumour suppressor in cancer.

show abstract

“…It was proposed that methylation-related aberrant ZAR1 expression was unlikely to be related to glioma tumorigenesis [16]. ZAR1 intragenic methylation (first exon to intron 1) in sporadic bladder cancer was decreased in high-grade vs. low-grade tumours [18]. In hepatitits C virus, positive hepatocellular carcinoma ZAR1 hypermethylation of exon 1 was found [19].…”

Section: Introductionmentioning

confidence: 99%

ZAR1 is a novel epigenetically inactivated tumour suppressor in lung cancer

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Identification of Frequent Differentially Methylated Region in Sporadic Bladder Cancers

Cited by 8 publications

References 15 publications

Bladder Tumor Heterogeneity: The Impact on Clinical Treatment

Bladder Tumor Heterogeneity: The Impact on Clinical Treatment

Epigenetic therapy of novel tumour suppressor ZAR1 and its cancer biomarker function

ZAR1 is a novel epigenetically inactivated tumour suppressor in lung cancer

Contact Info

Product

Resources

About