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

Michael Witcher, Beverly M. Emerson

Research output: Contribution to journalArticle

141 Scopus citations

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

Keywords

  • CELLCYCLE
  • DNA
  • HUMDISEASE

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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