Senescence and epigenetic dysregulation in cancer.
Mammalian cells have a finite proliferative lifespan, at the end of which they are unable to enter S phase in response to mitogenic stimuli. They undergo morphological changes and synthesize an altered repertoire of cell type-specific proteins. This non-proliferative state is termed replicative senescence and is regarded as a major tumor suppressor mechanism. The ability to overcome senescence and obtain a limitless replicative potential is called immortalization, and considered to be one of the prerequisites of cancer formation. While senescence mainly represents a genetically governed process, epigenetic changes in cancer have received increasing attention as an alternative mechanism for mediating gene expression changes in transformed cells. DNA methylation of promoter-containing CpG islands has emerged as an epigenetic mechanism of silencing tumor suppressor genes. New insights are being gained into the mechanisms causing aberrant methylation in cancer and evidence suggests that aging is accompanied by accumulation of cells with aberrant CpG island methylation. Aberrant methylation may contribute to many of the physiological and pathological changes associated with aging including tumor development. Finally, we describe how genes involved in promoting longevity might inhibit pathways promoting tumorigenesis.
Department of Development and Molecular Biology, Division of Hormone-Responsive Tumors, Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Peter
P
Neumeister
Chris
C
Albanese
Beate
B
Balent
John
J
Greally
Richard G
RG
Pestell
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology*; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*
D006657:Histones; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D004247:DNA; D019098:Telomerase; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases