Clinical epigenetics is the application of molecular biological techniques for detecting changes in DNA methylation or histone modification in order to diagnose or study disorders characterized by heritable defects in gene expression, e.g., transcription control by ENL YEATS domain in yeast [1] or the effect of depletion of SmarcB1 on myc network signaling on the development of Krasindependent pancreatic cancer cells [2].

Similarly, cancer epigenetics is the study of somatically heritable changes to molecular processes that influence the information flow between DNA of cancer cells and their gene expression which involves comparison between normal cells and cancers in DNA methylation, histone modifications in genes encoding epigenetic regulators as exemplified by recent report of chemical probe for dissecting the cancer epigenome [3]. Shorter telomeres have also been implicated in genomic instability and oncogenesis [4]. DNA damage is assumed to be the primary underlying cause of cancer and deficient DNA repair and epigenetic reduction in DNA repair. Cancer epigenetics can occur through a numbers of gene modification mechanisms including: DNA methylation (hyper-and hypomethylation) [5,6], decreased histone acetylation of nucleosomic octomers (H1-H2a/H3-H4)and by microRNA gene silencing, as miRNAs control about 60% of the transcriptional activity of protein encoding genes. Epigenetic control of chromosomal translocations product occurs in the Philadelphia (Ph) chromosome, in patient with Chronic Myelogenous Leukemia (CML). The subsequent 9q2 translocation results in the Abl oncogene activation. Finally, a number of compounds are considered epigenetic carcinogens and teratogens such as second-generation effects of diethylstilbestrol, arsenite, hexachlorobenzene and nickel compounds [7]. Further studies on mechanisms of cancer epigenetics are detailed in the following citations [8-15].

Little is known about the epigenetic events associated with exit of normal somatic cell from neither the proliferative state nor how it may differ in cancer cells. However, there is extensive literature concerning the epigenetic involvement of chromatin structure and remodeling, nuclease chromatic sensitivities, and chromatic histone protein modifications during the G1/S transition of normal somatic cells and the transition from the pluripotency cell cycle to the somatic cell proliferative state [16]. Are there epigenetic processes involved in states of cell cycle arrest?

Bacteria can enter a state of dormancy or spore formation of as yet there are no reports as such [17]. By contrast, there is a vast literature on the epigenetic control of mammalian cell senescence in both normal and cancer cells by cell cycle dependent histone deacetylase inhibitors in fibroblast cells [18]. Many reports involve the role of p53 tumor suppressor gene activation and high levels of p16 as mediated thru MEK/MAPK mitogenic signaling [19-23] Other epigenetic mechanism involve the over expression of ectopic RAS [24], telomere shortening [25], and finally, the role of WNT16B in human epidermal keratinocyte proliferation control [26]. What about reversible G₁ cell cycle arrest?

Recently, a single report [27] examined the patterns of global DNA methylation following G₁ growth arrest in normal and several different epidermoid cancer cell lines. They report that the 5-methylcytosine content of mouse embryonic fibroblast arrested by nutrient deficiency, serum deprivation, confluency arrest, and arrest at a novel cell differentiation restriction point were all hypermethylated relative to proliferating cultures. In addition, four different proliferating cultures of epidermoid cancer cell were hypomethylated relative to normal proliferating human epidermal keratinocytes, while two different squamous carcinoma cell lines were further hypomethylated by suspensioninduced growth arrest. These findings strongly support a role of epigenetic events in regulating switching states between proliferation and growth arrest.

References

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