Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers

Hagihara, Atsushi; Miyamoto, Kazuaki; Furuta, Junichi; Hiraoka, Nobuyoshi; Wakazono, Kuniko; Seki, Shuichi; Fukushima, Shoji; Tsao, Ming‐Sound; Sügimura, Takashi; Ushijima, Toshikazu

doi:10.1038/sj.onc.1207783

Cited by 113 publications

(114 citation statements)

References 29 publications

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“…The up-regulation of the BEX1 ( brain expressed X-linked 1 ) gene under combination therapy was of particular interest, as this encoded protein has been implicated as a tumor-suppressor gene (TSG) in various cellular contexts (33-35). Similarly, neuronal pentraxin-1 ( NPTX1 ), which is also strongly up-regulated in response to the combination therapy, has been described as a potential TSG or biomarker in a variety of cancer types (36-38). Quantitative real-time PCR (qRT-PCR) was used to validate the over-expression of BEX1 and NPTX1 RNA in these xenografts.…”

Section: Resultsmentioning

confidence: 99%

“…The WTS results for both BEX1 and NPTX1 were confirmed by qRT-PCR in the xenografts from the study, and the induction of BEX1 by the drug combination was also confirmed in IM-sensitive GIST-T1 and IM-resistant GIST430 cell lines, providing cellular models for exploring this finding. Numerous reports in the literature implicate BEX1 and NPTX1 as tumor-suppressor genes or biomarkers in various cancers (33-35,37,38). Both genes have been implicated in connection with pro-apoptotic pathways in different cellular contexts.…”

Section: Discussionmentioning

confidence: 99%

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Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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Purpose Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors. Experimental Design Here, we performed in vitro and in vivo studies evaluating the novel combination of IM with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. Results This drug combination demonstrated significant synergistic effects in a panel of IM-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in IM-sensitive GIST xenografts as compared to treatment with IM or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated in combination-treated tumors compared to tumors treated with the two monotherapies. Conclusion These studies provide strong preclinical justification for combining IM with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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“…Now, owing to completion of the sequencing of the human genome, it has become evident that, even if limited to CGI in promoter regions or putative promoter regions (5′ regions) of genes, most cancers have multiple aberrant methylations. (18)(19)(20)(21) These aberrant methylations are considered to provide a good source of tumor markers,…”

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confidence: 99%

“…As there are many excellent reviews on epigenetics and cancer, (1,3,10,22) here, we would like to focus on recent advancements on how aberrant DNA methylation is induced, based on our recent findings. (19)(20)(21)(25)(26)(27)(28)(29) Factors known to be associated with DNA methylation. Factors that are known to be associated with methylation of CGI include aging, chronic inflammation, and viral infections.…”

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confidence: 99%

Aberrant methylations in cancer cells: Where do they come from?

2005

Self Cite

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Cancer epigenetics is rapidly moving into a translational phase, and knowledge on how aberrant DNA methylation is induced is becoming important. Aging, chronic inflammation, and viral infections are known to promote methylation of non-core regions of promoter CpG islands (CGI). The non-core methylation and 'seeds of methylation', scattered methylation in a CGI, are considered to serve as triggers for dense methylation of a promoter CGI, which permanently represses expression of its downstream gene. Decreased gene transcription is an important factor that promotes induction of dense methylation. The presence of the CGI methylator phenotype (CIMP), in which methylation of multiple CGI was observed, is under dispute. Some gastric cancer cell lines have increased rates of de novo methylation, and neuroblastoma cases with CIMP show qualitatively different prognosis from those without. This strongly supports the presence of CIMP, but it seems to contain multiple entities. Limited knowledge is available for epimutagens, the chemicals that induce DNA demethylation or methylation. We have developed an assay system to detect demethylating agents, and an assay system for methylating agents is necessary. Efforts in the field on how aberrant methylation is induced will lead to new cancer prevention, diagnostics, and therapeutics. (1) The first example was identified for the RB gene in sporadic retinoblastomas in 1993 (2,3) followed by VHL, (4) CDKN2A ( p16 ), (5,6) CDH1 (E-cadherin), (7,8) and hMLH1.(9) Now, many tumorsuppressor genes are known to be inactivated by methylation of their promoter CGI in a wide variety of cancers.(1) Methylation of a promoter CGI excludes some methylation-sensitive transcription factors, such as CTCF, and recruits methyl-CpG binding proteins, such as MeCP2 and MBD1-MBD3.(10) These methyl-CpG binding proteins further recruit histone deacetylases, histone methyltransferases, and heterochromatin proteins.(11) It is believed that changes in chromatin structure will block the access of transcription complex to DNA, and repress transcription.In parallel with the mechanistic studies on how DNA methylation leads to gene silencing, the search for genomic regions aberrantly methylated in cancers has also made a lot of progress. (12) In the late 1990s, before the human genome sequence was available, several genome-wide screening methods were developed, such as restriction landmark genomic scanning-methylation, methylation-sensitive-representational difference analysis (MS-RDA), methylation-sensitive-arbitrarily primed PCR, and methylated CpG island amplification-RDA.(13 -17) These methods revealed that cancers harbor many aberrantly methylated genomic regions. Now, owing to completion of the sequencing of the human genome, it has become evident that, even if limited to CGI in promoter regions or putative promoter regions (5′ regions) of genes, most cancers have multiple aberrant methylations. (18)(19)(20)(21) These aberrant methylations are considered to provide a good source of tumor markers,and targets ...

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“…There are also reports to support the hypothesis that N-cadherin can be regulated by methylation. N-cadherin was among the 13 genes in which 5Ј CpG islands were methylated leading to silencing of the genes in primary pancreatic cancers (11); it is also dysregulated in thyroid carcinoma cell lines (14). Yamashita et al (38) found N-cadherin to be among the methylation-silenced genes in a gastric cancer cell line AGS.…”

Section: Discussionmentioning

confidence: 99%

Promoter methylation is associated with the age-dependent loss of N-cadherin in the rat kidney

Akintola¹,

Crislip²,

Catania³

et al. 2008

American Journal of Physiology-Renal Physiology

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Akintola AD, Crislip ZL, Catania JM, Chen G, Zimmer WE, Burghardt RC, Parrish AR. Promoter methylation is associated with the age-dependent loss of N-cadherin in the rat kidney. Am J Physiol Renal Physiol 294: F170-F176, 2008. First published October 24, 2007 doi:10.1152/ajprenal.00285.2007.-The cadherins are cell adhesion molecules required for cellular homeostasis, and N-cadherin is the predominant cadherin expressed in proximal tubular epithelial cells in humans and rats. Our laboratory previously reported an age-dependent decrease in renal N-cadherin expression; the levels of N-cadherin mRNA and protein expression decreased in parallel, implicating a transcriptional mechanism in the age-dependent loss of expression (19). In this study, we examined the hypothesis that promoter hypermethylation underlies the loss of N-cadherin expression in aging rat kidney. We cloned the 5Ј flanking region of the rat N-cadherin gene and observed basic promoter activity in a 3,992-bp region localized immediately upstream of the ATG start site. Nucleotide analysis revealed 87% identity with the human N-cadherin minimal promoter region. Consistent with a role for regulation by DNA methylation, we found that a dense CpG island, which spans 1,104 bp (Ϫ1,158 to Ϫ55), flanks the rat N-cadherin gene; a similar CpG profile was found in the human N-cadherin 5Ј flanking region. Methylation-specific PCR analysis demonstrated that the promoter region of N-cadherin is heavily methylated in aged, but not young, rat kidney. Interestingly, the promoter is not methylated in age-matched, calorically restricted animals. In contrast, the promoter region is not methylated in either young or aged rat liver; this corresponds to the finding that aging is not associated with decreased N-cadherin expression in the liver. In addition, N-cadherin expression is markedly induced in NRK-52E cells treated with the DNA methyltransferase inhibitor 5-aza-2Ј-deoxycytidine, further suggesting that methylation at CpG in the promoter region may underlie the age-dependent decrease in renal N-cadherin expression.

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Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers

Cited by 113 publications

References 29 publications

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Aberrant methylations in cancer cells: Where do they come from?

Promoter methylation is associated with the age-dependent loss of N-cadherin in the rat kidney

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