Cbx7 represses cancer stem cell phenotype in Tera2 through inhibition of Wnt signaling
Embargo until
Date
2014-03-26
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
Epigenetics has been defined as heritable changes in cell phenotypes and attendant gene expression patterns that do not directly alter the nucleic acid base sequence. Several interdependent processes are currently classified as epigenetic, such as DNA methylation, nuclear positioning and covalent modifications of histone proteins, interaction with non-coding RNA species, and higher order organization of nucleic acid in the nucleus. This thesis centers on the activities of key players in maintenance of epigenetic imposition of gene silencing, the repressive Polycomb group proteins and DNA methylation. Both mechanisms serve as major regulators of normal developmental processes and have interactive roles in cancer as potential mediators of abnormal gene silencing and associated altered DNA methylation of normally unmethylated regions such gene promoter CpG islands. Our lab has previously reported on the polycomb complex, PRC1, and specifically the protein CBX7, and its role in initiating DNA methylation at cancer-specific genes in Tera2 embryonal carcinoma cells. Tera2 has been shown to differentiate to neuronal cells in response to exposure to all-trans retinoic acid (ATRA), but in CBX7-overexpressing Tera2, a small “outgrowth” subpopulation exhibits retinoid resistance after 3 weeks of ATRA exposure. When withdrawn from ATRA exposure and subsequently re-exposed, the majority of Cbx7 outgrowth cells again show sensitivity to the differentiating effects of ATRA, but again forms a retinoid resistant subpopulation. The CBX7 and CBX7 outgrowth populations exhibit reduced tumorigenicity in NOD/SCID mice. We link CBX7 overexpression to suppression of both canonical and non-canonical Wnt signaling pathways, owing in part to transcriptional repression and associated DNA methylation of the LEF1 enhancer protein and cJUN transcription factor. In the above Tera2 model, the unresponsiveness of the Wnt pathway induced by CBX7 may represent an altered epigenetic state associated with a less tumorigenic state with a new pattern of cancer-specific promoter CpG island DNA hypermethylation.
Description
Keywords
Epigenetics, Polycomb