Demethylation of MAGE promoters during gastric cancer progression

Honda, Takao; Tamura, Gen; Waki, Takayoshi; Kawata, Satoshi; Terashima, Masanori; Nishizuka, Satoshi; Motoyama, Teiichi

doi:10.1038/sj.bjc.6601600

Cited by 85 publications

(61 citation statements)

References 34 publications

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“…Figure 4A also shows that this region of the MAGE-A1 gene was densely methylated in parental cells that do not normally express this gene. Previous studies showed that multiple CpGs located in the regulatory region of a gene must be substantially demethylated to make the promoter accessible for transcriptional machinery (28,(40)(41)(42)(43). We expected to see similar pattern induced by BORIS and/or 5-azadC on activation in NHDF.…”

Section: Resultsmentioning

confidence: 58%

Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis Genes

et al. 2005

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Brother of the Regulator of Imprinted Sites (BORIS) is a mammalian CTCF paralog with the same central 11Zn fingers (11ZF) that mediate specific interactions with varying f50-bp target sites. Regulated in vivo occupancy of such sites may yield structurally and functionally distinct CTCF/DNA complexes involved in various aspects of gene regulation, including epigenetic control of gene imprinting and X chromosome inactivation. The latter functions are mediated by meCpGsensitive 11ZF binding. Because CTCF is normally present in all somatic cells, whereas BORIS is active only in CTCF-and 5-methylcytosine-deficient adult male germ cells, switching DNA occupancy from CTCF to BORIS was suggested to regulate site specificity and timing of epigenetic reprogramming. In addition to 11ZF-binding paternal imprinting control regions, cancer-testis gene promoters also undergo remethylation during CTCF/BORIS switching in germ cells. Only promoters of cancer testis genes are normally silenced in all somatic cells but activated during spermatogenesis when demethylated in BORIS-positive germ cells and are found aberrantly derepressed in various tumors. We show here that BORIS is also expressed in multiple cancers and is thus itself a cancer-testis gene and that conditional expression of BORIS in normal fibroblasts activates cancer-testis genes selectively. We tested if replacement of CTCF by BORIS on regulatory DNA occurs in vivo on activation of a prototype cancer-testis gene, MAGE-A1. Transition from a hypermethylated/silenced to a hypomethylated/activated status induced in normal cells by 5-aza-2V -deoxycytidine (5-azadC) was mimicked by conditional input of BORIS and is associated with complete switching from CTCF to BORIS occupancy at a single 11ZF target. This site manifested a novel type of CTCF/BORIS 11ZF binding insensitive to CpG methylation. Whereas 5-azadC induction of BORIS takes only few hours, derepression of MAGE-A1 occurred 1 to 2 days later, suggesting that BORIS mediates cancer-testis gene activation by 5-azadC. Indeed, infection of normal fibroblasts with anti-BORIS short hairpin RNA retroviruses before treatment with 5-azadC blocked reactivation of MAGE-A1. We suggest that BORIS is likely tethering epigenetic machinery to a novel class of CTCF/BORIS 11ZF target sequences that mediate induction of cancer-testis genes. (Cancer Res 2005; 65(17): 7751-62)

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Section: Resultsmentioning

confidence: 58%

Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis Genes

et al. 2005

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“…For several germ cell and trophoblast-specific genes, it has been reported that their expression in cancer cells correlates with demethylation of CpG islands in the respective promoter regions (11,12,(22)(23)(24). Consequently, such genes are easily activated in nonexpressing cells by experimental genomic demethylation using compounds, such as 5-aza-2'-deoxycytidine.…”

Section: Resultsmentioning

confidence: 99%

A Placenta-Specific Gene Ectopically Activated in Many Human Cancers Is Essentially Involved in Malignant Cell Processes

Şahin²,

et al. 2007

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The identification and functional characterization of tumorspecific genes is a prerequisite for the development of targeted cancer therapies. Using an integrated data mining and experimental validation approach for the discovery of new targets for antibody therapy of cancer, we identified PLAC1. PLAC1 is a placenta-specific gene with no detectable expression in any other normal human tissue. However, it is frequently aberrantly activated and highly expressed in a variety of tumor types, in particular breast cancer. RNAimediated silencing of PLAC1 in MCF-7 and BT-549 breast cancer cells profoundly impairs motility, migration, and invasion and induces a G 1 -S cell cycle block with nearly complete abrogation of proliferation. Knockdown of PLAC1 is associated with decreased expression of cyclin D1 and reduced phosphorylation of AKT kinase. Moreover, PLAC1 is localized on the surface of cancer cells and is accessible for antibodies which antagonize biological functions of this molecule. These features, in summary, make PLAC1 an attractive candidate for targeted immunotherapeutic approaches. [Cancer Res 2007;67(19):9528-34]

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“…En efecto, en varias publicaciones se ha redescubierto a la hipometilación como un mecanismo de activación de oncogenes [50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66] . Estas publicaciones indican que la hipometilación de genes específicos, tales como MAGE 51 , synuclein-alfa 52 , MUC2 55 , maspin 57 , CAGE 56 y family A melanoma antigen 61 ocurriría en las etapas avanzadas del cáncer. Finalmente, la sobreexpresión de reconocidos oncogenes como Myc, H-ras y ciclina D1 54,60 también ha sido asociada a la hipometilación de sus regiones promotoras.…”

Section: Hipometilación Del Adn Y Cáncer Gástricounclassified

Bases epigenéticas del cáncer gástrico: oportunidades para la búsqueda de nuevos biomarcadores

2013

Rev. méd. Chile

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Epigenetics in the pathogenesis and early detection of gastric cancerpuc.cl E l cáncer gástrico es la primera causa de muerte por enfermedades neoplásicas en Chile y la segunda en el mundo 1,2 . A pesar de los avances en el tratamiento y una disminución de sus lesiones precursoras 3,4 , recientes publicaciones sugieren un probable aumento de su mortalidad, particularmente en población joven 5 . Estas observaciones, en conjunto con proyecciones de la mortalidad global para los próximos 20 años, sugieren que el cáncer gástrico ocupará la décima causa global de muerte para la década del 2030 6 . El cáncer gástrico se puede clasificar según aspectos clínicos, endoscópicos o histológicos 7-13 . La clasificación más utilizada es la propuesta por Lauren 13 , la cual, según parámetros histológicos, define dos tipos de cáncer gástrico: el intestinal y el difuso. El primero se caracteriza por la formación de estructuras glandulares que semejan la mucosa colónica y que está precedida por una secuencia de lesiones muy bien caracterizadas por Correa y col. 14,15 . Por otra parte, el cáncer gástrico de tipo difuso, no forma estructuras histológicas y en consecuencia no tiene lesiones precursoras reconocidas 16 . Una particularidad importante de la clasificación de Lauren es que ha sido muy útil para estudiar el rol del ambiente, en particular en la variante intestinal 15 . En este sentido, las lesiones precancerosas han demostrado progresar de forma dinámica, desde la gastritis crónica superficial, gastritis crónica atrófica, metaplasia intestinal y finalmente displasia. Estos eventos constituyen las bases del "modelo humano de cáncer gástrico" postulado por Correa 17 . Una de las características fundamentales de este modelo es que junto con identificar una secuencia progresiva de lesiones, señala también la existencia de progresión/regresión de estas lesiones.

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Demethylation of MAGE promoters during gastric cancer progression

Cited by 85 publications

References 34 publications

Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis Genes

Conditional Expression of the CTCF-Paralogous Transcriptional Factor BORIS in Normal Cells Results in Demethylation and Derepression of MAGE-A1 and Reactivation of Other Cancer-Testis Genes

A Placenta-Specific Gene Ectopically Activated in Many Human Cancers Is Essentially Involved in Malignant Cell Processes

Bases epigenéticas del cáncer gástrico: oportunidades para la búsqueda de nuevos biomarcadores

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