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.

Highlights

  • It is widely recognized that tumours and tumour-derived cell lines exhibit altered patterns of DNA methylation and gene expression in comparison with normal tissues and primary cells

  • There are many specific examples of silencing of tumour suppressor genes by promoter DNA methylation, recent high-throughput analyses in breast, colorectal and other types of cancer have suggested that the vast majority of gene promoters methylated in tumours represent developmentally regulated loci, which are already repressed in pre-cancerous tissues [36,37]

  • These observations highlight the coexistence of ‘driver’ and ‘passenger’ de novo methylation events that occur in tumours implying that most changes in DNA methylation at gene promoters are unlikely to contribute to cancer formation [15,38,39]

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Summary

Introduction

It is widely recognized that tumours and tumour-derived cell lines exhibit altered patterns of DNA methylation and gene expression in comparison with normal tissues and primary cells. Gain of DNA methylation at normally DNA methylation-free gene promoters and extensive loss of DNA methylation throughout the genome have been detected in a variety of tumour types [1,2,3,4]. Loss of DNA methylation from repetitive sequences is thought to promote genomic instability, which often accompanies cancer progression [5,6]. The vast majority of epigenetic studies on human cancers are carried out either on limited amount of clinical material isolated from patients when the disease is well advanced or on cell lines established from tumours and maintained in culture for extended periods of time.

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