Epigenetic Silencing of the p16INK4a Tumor Suppressor Is Associated with Loss of CTCF Binding and a Chromatin Boundary

Michael Witcher, Beverly Emerson

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

The p16INK4a tumor suppressor gene is a frequent target of epigenetic inactivation in human cancers, which is an early event in breast carcinogenesis. We describe the existence of a chromatin boundary upstream of the p16 gene that is lost when this gene is aberrantly silenced. We show that the multifunctional protein CTCF associates in the vicinity of this boundary and absence of binding strongly coincides with p16 silencing in multiple types of cancer cells. CTCF binding also correlates with RASSF1A and CDH1 gene activation, and CTCF interaction is absent when these genes are methylated and silenced. Interestingly, defective poly(ADP-ribosyl)ation of CTCF and dissociation from the molecular chaperone Nucleolin occur in p16-silenced cells, abrogating its proper function. Thus, destabilization of specific chromosomal boundaries through aberrant crosstalk between CTCF, poly(ADP-ribosyl)ation, and DNA methylation may be a general mechanism to inactivate tumor suppressor genes and initiate tumorigenesis in numerous forms of human cancers.

Original languageEnglish (US)
Pages (from-to)271-284
Number of pages14
JournalMolecular Cell
Volume34
Issue number3
DOIs
StatePublished - May 15 2009
Externally publishedYes

Fingerprint

Epigenomics
Chromatin
Tumor Suppressor Genes
Adenosine Diphosphate
Carcinogenesis
p16 Genes
Neoplasms
Molecular Chaperones
DNA Methylation
Transcriptional Activation
Genes
Breast

Keywords

  • CELLCYCLE
  • DNA
  • HUMDISEASE

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Epigenetic Silencing of the p16INK4a Tumor Suppressor Is Associated with Loss of CTCF Binding and a Chromatin Boundary. / Witcher, Michael; Emerson, Beverly.

In: Molecular Cell, Vol. 34, No. 3, 15.05.2009, p. 271-284.

Research output: Contribution to journalArticle

@article{4f2a26e5a24047b190c8beadf084d4d8,
title = "Epigenetic Silencing of the p16INK4a Tumor Suppressor Is Associated with Loss of CTCF Binding and a Chromatin Boundary",
abstract = "The p16INK4a tumor suppressor gene is a frequent target of epigenetic inactivation in human cancers, which is an early event in breast carcinogenesis. We describe the existence of a chromatin boundary upstream of the p16 gene that is lost when this gene is aberrantly silenced. We show that the multifunctional protein CTCF associates in the vicinity of this boundary and absence of binding strongly coincides with p16 silencing in multiple types of cancer cells. CTCF binding also correlates with RASSF1A and CDH1 gene activation, and CTCF interaction is absent when these genes are methylated and silenced. Interestingly, defective poly(ADP-ribosyl)ation of CTCF and dissociation from the molecular chaperone Nucleolin occur in p16-silenced cells, abrogating its proper function. Thus, destabilization of specific chromosomal boundaries through aberrant crosstalk between CTCF, poly(ADP-ribosyl)ation, and DNA methylation may be a general mechanism to inactivate tumor suppressor genes and initiate tumorigenesis in numerous forms of human cancers.",
keywords = "CELLCYCLE, DNA, HUMDISEASE",
author = "Michael Witcher and Beverly Emerson",
year = "2009",
month = "5",
day = "15",
doi = "10.1016/j.molcel.2009.04.001",
language = "English (US)",
volume = "34",
pages = "271--284",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Epigenetic Silencing of the p16INK4a Tumor Suppressor Is Associated with Loss of CTCF Binding and a Chromatin Boundary

AU - Witcher, Michael

AU - Emerson, Beverly

PY - 2009/5/15

Y1 - 2009/5/15

N2 - The p16INK4a tumor suppressor gene is a frequent target of epigenetic inactivation in human cancers, which is an early event in breast carcinogenesis. We describe the existence of a chromatin boundary upstream of the p16 gene that is lost when this gene is aberrantly silenced. We show that the multifunctional protein CTCF associates in the vicinity of this boundary and absence of binding strongly coincides with p16 silencing in multiple types of cancer cells. CTCF binding also correlates with RASSF1A and CDH1 gene activation, and CTCF interaction is absent when these genes are methylated and silenced. Interestingly, defective poly(ADP-ribosyl)ation of CTCF and dissociation from the molecular chaperone Nucleolin occur in p16-silenced cells, abrogating its proper function. Thus, destabilization of specific chromosomal boundaries through aberrant crosstalk between CTCF, poly(ADP-ribosyl)ation, and DNA methylation may be a general mechanism to inactivate tumor suppressor genes and initiate tumorigenesis in numerous forms of human cancers.

AB - The p16INK4a tumor suppressor gene is a frequent target of epigenetic inactivation in human cancers, which is an early event in breast carcinogenesis. We describe the existence of a chromatin boundary upstream of the p16 gene that is lost when this gene is aberrantly silenced. We show that the multifunctional protein CTCF associates in the vicinity of this boundary and absence of binding strongly coincides with p16 silencing in multiple types of cancer cells. CTCF binding also correlates with RASSF1A and CDH1 gene activation, and CTCF interaction is absent when these genes are methylated and silenced. Interestingly, defective poly(ADP-ribosyl)ation of CTCF and dissociation from the molecular chaperone Nucleolin occur in p16-silenced cells, abrogating its proper function. Thus, destabilization of specific chromosomal boundaries through aberrant crosstalk between CTCF, poly(ADP-ribosyl)ation, and DNA methylation may be a general mechanism to inactivate tumor suppressor genes and initiate tumorigenesis in numerous forms of human cancers.

KW - CELLCYCLE

KW - DNA

KW - HUMDISEASE

UR - http://www.scopus.com/inward/record.url?scp=65549159993&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65549159993&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2009.04.001

DO - 10.1016/j.molcel.2009.04.001

M3 - Article

VL - 34

SP - 271

EP - 284

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -