title: Mammalian cells acquire epigenetic hallmarks of human cancer during immortalization.
abstract: Progression to malignancy requires that cells overcome senescence and switch to an immortal phenotype. Thus, exploring the genetic and epigenetic changes that occur during senescence/immortalization may help elucidate crucial events that lead to cell transformation. In the present study, we have globally profiled DNA methylation in relation to gene expression in primary, senescent and immortalized mouse embryonic fibroblasts. Using a high-resolution genome-wide mapping technique, followed by extensive locus-specific validation assays, we have identified 24 CpG islands that display significantly higher levels of CpG methylation in immortalized cell lines as compared to primary murine fibroblasts. Several of these hypermethylated CpG islands are associated with genes involved in the MEK-ERK pathway, one of the most frequently disrupted pathways in cancer. Approximately half of the hypermethylated targets are developmental regulators, and bind to the repressive Polycomb group (PcG) proteins, often in the context of bivalent chromatin in mouse embryonic stem cells. Because PcG-associated aberrant DNA methylation is a hallmark of several human malignancies, our methylation data suggest that epigenetic reprogramming of pluripotency genes may initiate cell immortalization. Consistent with methylome alterations, global gene expression analysis reveals that the vast majority of genes dysregulated during cell immortalization belongs to gene families that converge into the MEK-ERK pathway. Additionally, several dysregulated members of the MAP kinase network show concomitant hypermethylation of CpG islands. Unlocking alternative epigenetic routes for cell immortalization will be paramount for understanding crucial events leading to cell transformation. Unlike genetic alterations, epigenetic changes are reversible events, and as such, can be amenable to pharmacological interventions, which makes them appealing targets for cancer therapy when genetic approaches prove inadequate.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Tommasi
authors.forename: Albert
authors.initials: A
authors.lastname: Zheng
authors.forename: Annette
authors.initials: A
authors.lastname: Weninger
authors.forename: Steven E
authors.initials: SE
authors.lastname: Bates
authors.forename: Xuejun Arthur
authors.initials: XA
authors.lastname: Li
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.forename: Monica
authors.initials: M
authors.lastname: Hollstein
authors.forename: Ahmad
authors.initials: A
authors.lastname: Besaratinia
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D018899:CpG Islands; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D004247:DNA