Immortality, but not oncogenic transformation, of primary human cells leads to epigenetic reprogramming of DNA methylation and gene expression

Gordon, Katrina; Clouaire, Thomas; Bao, Xun X.; Kemp, Sadie E.; Xenophontos, Maria; de Las Heras, Jose Ignacio; Stancheva, Irina

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.

Citation

Gordon, K., Clouaire, T., Bao, X. X., Kemp, S. E., Xenophontos, M., de Las Heras, J. I., & Stancheva, I. (2014). Immortality, but not oncogenic transformation, of primary human cells leads to epigenetic reprogramming of DNA methylation and gene expression. Nucleic Acids Research, 42(6), 3529-3541. https://doi.org/10.1093/nar/gkt1351

• Journal Article Type: Article
• Acceptance Date: Dec 5, 2013
• Online Publication Date: Dec 26, 2013
• Publication Date: Apr 1, 2014
• Deposit Date: Feb 16, 2017
• Publicly Available Date: Feb 16, 2017
• Journal: Nucleic Acids Research
• Print ISSN: 0305-1048
• Electronic ISSN: 1362-4962
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 42
• Issue: 6
• Pages: 3529-3541
• DOI: https://doi.org/10.1093/nar/gkt1351
• Keywords: gene expression, cancer, cell line, dna, dna methylation, oncogenes, epigenetics, atm gene,
• Public URL: http://researchrepository.napier.ac.uk/Output/685976
• Contract Date: Feb 16, 2017