Abstract 118: CTCF, a master epigenetic regulator, is a haploinsufficient tumor suppressor gene in multiple cell lineages

Abstract

Abstract While changes in the epigenetic landscape are ubiquitous in cancer, the origin and causal effects of most of these changes on neoplastic progression are largely unknown. The DNA binding protein Ctcf, regulates a diverse array of epigenetic processes, including DNA methylation spreading, but is role in cancer is unclear. Here we show that Ctcf heterozygous knockout mice are remarkably susceptible to spontaneous, ionizing radiation, and chemically-induced neoplasia in a broad range of tissues. Analysis of lung tumors from Ctcf+/− mice establishes Ctcf as a haploinsufficient tumor suppressor gene whose loss cooperates with mutant Kras to accelerate tumor growth and malignant progression. Increased DNA methylation at Ctcf binding sites in normal tissues from Ctcf+/− mice indicates that reduction of Ctcf leads to epigenetic deregulation and this occurs prior to overt neoplastic transformation. This indicates epigenetic instability can predispose a broad range of tissues to neoplastic transformation. A mouse model of Ctcf regulated epigenetic stability provides a useful setting to dissect the mechanistic link between environmental exposure, and risk of cancer or other diseases with an epigenetic component. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 118. doi:1538-7445.AM2012-118