title: Immortality, but not oncogenic transformation, of primary human cells leads to epigenetic reprogramming of DNA methylation and gene expression.
abstract: Tumourigenic transformation of normal cells into cancer typically involves several steps resulting in acquisition of unlimited growth potential, evasion of apoptosis and non-responsiveness to growth inhibitory signals. Both genetic and epigenetic changes can contribute to cancer development and progression. Given the vast genetic heterogeneity of human cancers and difficulty to monitor cancer-initiating events in vivo, the precise relationship between acquisition of genetic mutations and the temporal progression of epigenetic alterations in transformed cells is largely unclear. Here, we use an in vitro model system to investigate the contribution of cellular immortality and oncogenic transformation of primary human cells to epigenetic reprogramming of DNA methylation and gene expression. Our data demonstrate that extension of replicative life span of the cells is sufficient to induce accumulation of DNA methylation at gene promoters and large-scale changes in gene expression in a time-dependent manner. In contrast, continuous expression of cooperating oncogenes in immortalized cells, although essential for anchorage-independent growth and evasion of apoptosis, does not affect de novo DNA methylation at promoters and induces subtle expression changes. Taken together, these observations imply that cellular immortality promotes epigenetic adaptation to highly proliferative state, whereas transforming oncogenes confer additional properties to transformed human cells.
authors.affiliation: Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Michael Swann Building, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: Katrina
authors.initials: K
authors.lastname: Gordon
authors.forename: Thomas
authors.initials: T
authors.lastname: Clouaire
authors.forename: Xun X
authors.initials: XX
authors.lastname: Bao
authors.forename: Sadie E
authors.initials: SE
authors.lastname: Kemp
authors.forename: Maria
authors.initials: M
authors.lastname: Xenophontos
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: de Las Heras
authors.forename: Irina
authors.initials: I
authors.lastname: Stancheva
mesh_terms: D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D009857:Oncogenes; D011401:Promoter Regions, Genetic