Epigenetic regulation of the human retinoblastoma tumor suppressor gene promoter by CTCF

Epigenetic misregulation is a more common feature in human cancer than previously anticipated. In the present investigation, we identified CCCTC-binding factor (CTCF), the multivalent 11-zinc-finger nuclear factor, as a regulator that favors a particular local chromatin conformation of the human ret...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2007-03, Vol.67 (6), p.2577-2585
Main Authors: DE LA ROSA-VELAZQUEZ, Inti A, RINCON-ARANO, Héctor, BENITEZ-BRIBIESCA, Luis, RECILLAS-TARGA, Félix
Format: Article
Language:English
Subjects:
Antineoplastic agents
Base Sequence
Binding Sites
Biological and medical sciences
CCCTC-Binding Factor
CpG Islands
DNA Methylation
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Retinoblastoma
HeLa Cells
Humans
K562 Cells
Medical sciences
Molecular Sequence Data
Pharmacology. Drug treatments
Promoter Regions, Genetic
Repressor Proteins - genetics
Repressor Proteins - metabolism
RNA Interference
Transcription Factors - metabolism
Transgenes
Tumors
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Summary:Epigenetic misregulation is a more common feature in human cancer than previously anticipated. In the present investigation, we identified CCCTC-binding factor (CTCF), the multivalent 11-zinc-finger nuclear factor, as a regulator that favors a particular local chromatin conformation of the human retinoblastoma gene promoter. We show that its binding contributes to Rb gene promoter epigenetic stability. Ablation of the CTCF binding site from the human Rb gene promoter induced a rapid epigenetic silencing of reporter gene expression in an integrated genome context. CTCF DNA binding is methylation sensitive, and the methylated Rb-CTCF site is recognized by the Kaiso methyl-CpG-binding protein. This is the first evidence suggesting that CTCF protects the Rb gene promoter, a classic CpG island, against DNA methylation, and when such control region is abnormally methylated Kaiso, and probably its associated repressor complex, induce epigenetic silencing of the promoter. Our results identify CTCF as a novel epigenetic regulator of the human retinoblastoma gene promoter.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-06-2024