The true understanding of epigenetics evolved over time as our knowledge on DNA methylation and chromatin modifications and their effects on gene expression increased. The current flurry of research on epigenetics and the increasing documentation of the effects of various environmental factors on DNA methylation, chromatin modification, as well as on the expression of small non-coding RNAs (ncRNAs) have expanded the scope of research on the etiology of various diseases including cancer. The current review briefly discusses various molecular mechanisms of epigenetic regulation of gene expression, and expands the discussion with examples of heavy metal-induced alterations of gene expression and the associated epigenetic changes.

BackgroundType 1 diabetes (T1D) has been associated with a higher fracture risk due to alterations in bone structure and metabolism. On the other hand, the important role of the RANKL/OPG/RANK signaling axis in bone physiology is well established. The aim of this study was to evaluate the levels of receptor activator of nuclear factor kappa-B ligand (RANKL), receptor activator of nuclear factor kappa-B (RANK) and plasma osteoprotegerin (OPG) levels, in T1D youngsters and to investigate factors that could influence the OPG/RANK/RANKL signaling axis such as 25-hydroxy vitamin D [25(OH) D], parathormone (PTH) and age.MethodsSerum RANKL, RANK, 25(OH) D, PTH levels and plasma OPG levels, were measured in 71 youngsters with T1D and 50 healthy controls matched for age and gender.ResultsPlasma OPG levels were significantly lower (p = 0.025) in T1D patients compared to controls. Serum RANKL levels were significantly higher (p = 0.037), while no differences were observed in serum RANK levels (p = 0.946) between the two groups. Serum 25(OH) D levels found significantly decreased (p < 0.001) while serum PTH levels were significantly elevated (p < 0.001) in T1D patients than in controls.ConclusionsOur results demonstrated that OPG and RANKL may be promising biomarkers for T1D patients. However, their circulating levels were associated with several factors including PTH, 25(OH) D and therefore, may represent an integrative biomarker for a variety of endocrine signaling disturbances observed in T1D.

Modification of p53 expression levels and its principle apoptosis and cell cycle regulatory partners, mouse double minute 2 homolog (MDM-2) and p21, has been previously reported in various types of cancer. In the current study, the expression of Δ133p53 isoforms was investigated in lung carcinomas with respect to the expression of the aforementioned genes. The expression of p53 full-length transcript and Δ133p53 isoforms α, β and γ transcripts, MDM-2 and p21 transcripts were determined by reverse transcription-quantitative polymerase chain reaction, in total RNA isolated from 17 lung carcinoma specimens and 17 corresponding adjacent non-cancerous tissues. RNA expression analysis was performed according to the Pfaffl equation and Rest tool using β-actin as a reference gene. Detection of the above proteins was additionally performed by western blotting. Significant overexpression of the Δ133p53 mRNAs was observed in cancerous as compared with adjacent non-cancerous tissues (3.94-fold), whereas full-length p53 and MDM-2 expression exhibited a smaller, however significant, increase. The expression of the p21 transcript was significantly reduced in cancerous specimens. Δ133p53 and p21 expression levels varied in parallel, however were not significantly correlated. p53 full-length protein expression observed by western blot analysis strongly varied from the Δ133p53 isoforms, however MDM-2 protein isoforms were not detectable and p21 protein was more abundant in non-cancerous tissues. In conclusion, Δ133p53 mRNA levels is suggested as a potentially useful marker of malignancy in lung cancer. The absence of Δ133p53 protein in lung carcinomas, which overexpress Δ133p53 transcripts, may indicate the role of the latter in post-transcriptional regulation through RNA interference in the cell cycle and apoptosis.

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Analysis of germline p53 mutations in breast cancer reveals that the Li-Fraumeni and Li-Fraumeni-like syndromes are mostly related to the loss of initiation codon 133 of regulatory TP53 isoforms (Delta133p53). In eight codons of exons 5-8 (including 133), mutations are frequent in Li-Fraumeni-related, but scarce in sporadic breast cancer, while in six more codons they are frequent both in familial and sporadic breast cancers. At the proximity of these codons, we observed in somatic mutation databases, 16 codons (minihotspots mostly in exons 7, 8) which undergo frequent G:C > A:T transitions (non-CpG) in all sporadic cancers. In addition, in sporadic breast cancer we observed 35 adjacent codons in which the following types of mutation are observed: frequent G:C > A:T transitions at CCs/GGs, frequent silent mutations in exons 5,6 and suppressed nonsense mutations (5 codons, few records). Non-CpG G:C > A:T transitions in the 35 codons are rare in familial cancers (p53, BRCA1, or BRCA2-related), but frequent in sporadic cancers in organs where Li-Fraumeni-related carcinogenesis is common e.g. adrenal cortex, soft tissues. These data are in support of the following tissue-specific processes: in sporadic breast cancer (sarcomas etc.), loss of methylation sites (in 35 codons mostly next to codon 133), might lead to loss of silencing of TP53 isoforms which are suppressed in these tissues. On the contrary, "spreading" of cytosine methylation (asymmetric) in a G:C-rich region next to common hotspots (codons 238-252 in minihotspots) and mutagenesis probably destabilizes all tissues. Frequent C > T activation at non-CpG is also observed in prostate sporadic cancer, which similarly to breast, undergoes age-related crisis. The above data reveal that tissue-specific epigenetic regulatory mechanisms might be involved in p53 instability.