Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2002-04-18

AUTHORS

Takefumi Kikuchi, Minoru Toyota, Fumio Itoh, Hiromu Suzuki, Toshiro Obata, Hiroyuki Yamamoto, Hideki Kakiuchi, Masanobu Kusano, Jean-Pierre J Issa, Takashi Tokino, Kohzoh Imai

ABSTRACT

To clarify the role of DNA methylation in the silencing of the expression of cyclin-dependent kinase inhibitor p57KIP2 seen in certain tumors, we investigated the methylation status of its 5′ CpG island in various tumor cell lines and primary cancers. Dense methylation of the region around the transcription start site was detected in 1 out of 10 colorectal, 2 out of 8 gastric, and 6 out of 14 hematopoietic tumor cell lines and in 5 out of 35 (14%) gastric, 6 out of 20 (30%) hepatocellular, and 2 out of 18 (11%) pancreatic cancers; 7 out of 25 (28%) acute myeloid leukemia cases also showed methylation of the p57KIP2 gene, which strongly correlated with the CpG island methylator phenotype (P<0.001). Detailed mapping revealed that dense methylation of the region around the transcription start site (−300 to +400), but not of the edges of the CpG island, was closely associated with gene silencing. 5-aza-2′-deoxycytidine, a methyltransferase inhibitor, restored expression of p57KIP2, and chromatin immunoprecipitation using anti-histone H3 and H4 antibodies showed histone to be deacetylated in cell lines where p57KIP2 was methylated at the transcription start site. Regional methylation and histone deacetylation thus appear to be crucially involved in the silencing of p57KIP2 expression in human tumors. More... »

PAGES

2741-2749

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1205376

DOI

http://dx.doi.org/10.1038/sj.onc.1205376

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1015014986

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/11965547


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36 schema:description To clarify the role of DNA methylation in the silencing of the expression of cyclin-dependent kinase inhibitor p57KIP2 seen in certain tumors, we investigated the methylation status of its 5′ CpG island in various tumor cell lines and primary cancers. Dense methylation of the region around the transcription start site was detected in 1 out of 10 colorectal, 2 out of 8 gastric, and 6 out of 14 hematopoietic tumor cell lines and in 5 out of 35 (14%) gastric, 6 out of 20 (30%) hepatocellular, and 2 out of 18 (11%) pancreatic cancers; 7 out of 25 (28%) acute myeloid leukemia cases also showed methylation of the p57KIP2 gene, which strongly correlated with the CpG island methylator phenotype (P<0.001). Detailed mapping revealed that dense methylation of the region around the transcription start site (−300 to +400), but not of the edges of the CpG island, was closely associated with gene silencing. 5-aza-2′-deoxycytidine, a methyltransferase inhibitor, restored expression of p57KIP2, and chromatin immunoprecipitation using anti-histone H3 and H4 antibodies showed histone to be deacetylated in cell lines where p57KIP2 was methylated at the transcription start site. Regional methylation and histone deacetylation thus appear to be crucially involved in the silencing of p57KIP2 expression in human tumors.
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42 schema:keywords CpG island methylator phenotype
43 CpG islands
44 DNA methylation
45 H3
46 H4 antibodies
47 acute myeloid leukemia cases
48 antibodies
49 cancer
50 cases
51 cell lines
52 certain tumors
53 chromatin immunoprecipitation
54 colorectal
55 cyclin-dependent kinase inhibitor p57Kip2
56 deacetylation
57 dense methylation
58 detailed mapping
59 edge
60 expression
61 expression of p57Kip2
62 gastric
63 genes
64 hematopoietic tumor cell lines
65 hepatocellular
66 histone deacetylation
67 histones
68 human tumors
69 hypermethylation
70 immunoprecipitation
71 inactivation
72 inhibitors
73 islands
74 leukemia cases
75 lines
76 mapping
77 methylation
78 methylation status
79 methylator phenotype
80 methyltransferase inhibitor
81 myeloid leukemia cases
82 p57KIP2
83 p57KIP2 expression
84 p57KIP2 gene
85 pancreatic cancer
86 phenotype
87 primary cancer
88 promoter hypermethylation
89 region
90 regional methylation
91 role
92 silencing
93 sites
94 start site
95 status
96 transcription start site
97 tumor cell lines
98 tumors
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