CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2014 May 6

PMID 24794443

Citations 114

Authors

Christopher J Kemp

James M Moore

Russell Moser

Brady Bernard

Matt Teater

Leslie E Smith

Natalia A Rabaia

Kay E Gurley

Justin Guinney

Stephanie E Busch

Rita Shaknovich

Victor V Lobanenkov

Denny Liggitt

Ilya Shmulevich

Ari Melnick

Galina N Filippova

Affiliations

Soon will be listed here.

Abstract

Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. CTCF, a DNA-binding protein that regulates higher-order chromatin organization, is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here, we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation-, and chemically induced cancer in a broad range of tissues. Ctcf(+/-) tumors are characterized by increased aggressiveness, including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf(+/-) tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome wide. These findings establish CTCF as a prominent tumor-suppressor gene and point to CTCF-mediated epigenetic stability as a major barrier to neoplastic progression.

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