CTCF Haploinsufficiency Predisposes to Cancer by Destabilizing DNA Methylation

July 18, 2014

Humans are diploid organisms, meaning they inherit one set of chromosomes from each parent. One copy of the gene that encodes the DNA binding protein, CCCTC-binding factor (CTCF), is commonly deleted or mutated in some human cancers. CTCF alters chromatin structure, and thus gene expression, by regulating a DNA chemical modification process called methylation. Although a causal role for CTCF alterations in cancer had not been previously established, CTD2 investigators at the Fred Hutchison Cancer Research Center recently discovered that CTCF is implicated in tumor suppression, and loss of one copy increases cancer risk in mice.

Mice with just one copy of Ctcf (i.e., hemizygous) were susceptible to tumor formation in a variety of tissue types. These tumor tissues retained Ctcf mRNA and protein expression, which suggests Ctcf is haploinsufficient for tumor suppression. This means two normal copies of the gene need to be expressed to prevent tumor formation in mice. The researchers identified hypermethylation as a mechanism that may drive cancer susceptibility when Ctcf is reduced.

In support of these findings, mining data from The Cancer Genome Atlas revealed subtypes of human breast and endometrial cancers with CTCF copy number alterations/mutations that have altered DNA methylation patterns. CTCF alterations also correlated with poor outcome in endometrial tumors, but more research is needed to determine if CTCF haploinsufficiency corresponds to outcome in other subtypes and if CTCF will be a plausible therapeutic target.

Program:
CTD²
Last updated: October 30, 2018