Alhosin et al. Journal of Experimental & Clinical Cancer Research 2011, 30:41 http://www.jeccr.com/content/30/1/41 Page 2 of 10 Concerning cancer and transgenerational epigenetic effect of diets, in terms of increased risk, no evidence has so far yet been reported. However, cancerogenesis is now recognised as being the result of profound dietary- influenced epigenetic modifications, among which hypermethylation of the promoters of several TSGs occupies a main place [3,10]. Reversing promoter methylation of silenced tumor suppressor genes repre- sents a current challenge for anti-cancer therapy. 2. DNA methylation and histone modifications in cancer In mammalians, DNA methylation is the most widely studied epigenetic modification. It is mediated by a family of DNA methyltransferases (DNMTs) that trans- fer a methyl group (CH3) from the methyl donor S-ade- nosylmethionine at the carbon in the fifth position of cytosine in CpG dinucleotides [11,12]. This family includes several members, i.e. DNMT1, DNMT3A and DNMT3B [13]. DNMT2 and DNMT3L have very little methyltransferase activity and will not be discussed here [13]. While about 80% of isolated CpG sites in the gen- ome are methylated, the « CpG islands » (CpG-rich short regions of DNA) are usually unmethylated [14]. Exceptions are some CpG island promoters which remain methylated during development. X-chromosome inactivation and imprinted genes are the two known examples of these exceptions [15]. In cancer cells, in contrast to genome-wide hypomethylation which increases genomic instability and activates growth-pro- moting genes (proto-oncogenes), promoters of tumour suppressor genes are frequently hypermethylated and this contributes to carcinogenesis [16]. Various TSGs are silenced in cancer cells by promoter hypermethyla- tion such as RB1, H1C1 (Hypermethylated In Cancer 1), p16INK4A, MLH1 (Human Mutant L homologue 1), BRCA1 (BReast CAncer 1) and p73 [17-23]. While the capacity of CpG island hypermethylation to induce TSGs silencing is well studied, the mechanism by which these TSGs are specifically targeted is still unclear. One hypothesis is that CpG island hypermethylation of TSGs is driven by a mechanism involving unknown DNA binding factors that selectively recruit DNMT1 to the promoters of TSGs which will lead to pathological hypermethylation and subsequently to unpaired apoptosis. Many evidences of the crosstalk between DNA methy- lation and histone modifications have been reported [24,25]. The most important histones modifications, having effects on gene expression, are located on histone H3 and histone H4 [26]. One of them, that is known to have a gene silencing role and to have a strong relation- ship with DNA methylation, is the di- or tri-methylation of lysine 9 of histone 3 (H3K9me2 or H3K9me3). But methylation on the same histone on lysine 4 (H3K4me) is related to gene activation. All these modifications are catalysed by a broad variety of specific enzymes, some of which can catalyse the same reaction but at different location in the nucleus, i.e., heterochromatin or euchro- matin [26]. Histones undergo specific changes in their acetylation and methylation degrees during cancerogenesis [27]. Both deacetylation of H4K16 and accumulation of H3K9me2 are found on many repressed genes, including TSGs [27,28]. These modifications are mediated by HDACs (histone deacetylases) and G9a (histone 3 methyltransferase) respectively. HDACs are often over- expressed in various types of cancer such as renal can- cer [29] or gastric cancer [30] and have become essen- tial targets for anticancer therapy. G9a is co-localized near the methylated promoters of numerous genes in cancer cells [31]. Interestingly, it has been found that the inhibition of G9a is sufficient to induce a reactiva- tion of TSGs [32]. Therefore, over-expression of enzymes catalysing histone modifications (epigenetic writers), might be one explanation for the occurrence of altered epigenetic marks found in cancer. There is increasing evidence that Ubiquitin-like con- taining PHD Ring Finger 1 (UHRF1, also known as ICBP90 or Np95) plays a fundamental role in these pro- cesses by being involved in DNA methylation, histone methylation, histone acetylation, cell proliferation and apoptosis. This is due to the fact that UHRF1 possesses several domains (Figure 1) able to read both DNA methylation and histone methylation, thus, physically linking these two epigenetic marks [26,33,34]. 3. UHRF1 and DNA methylation and histone modifications patterns UHRF1, a putative oncogenic factor, is over-expressed in numerous cancers [35,36] and has been suggested to be an important biomarker to discriminate between cervical high-grade and low-grade cancer lesions [37]. Another study has highlighted the efficiency of UHRF1 as a mar- ker to differentially diagnose pancreatic adenocarcinoma, chronic pancreatitis and normal pancreas [38]. UHRF1 over-expression was also found in bladder cancer and the intensity of its over-expression appears to be related to the stage of the cancer [39], suggesting that the pre- sence of UHRF1 in urine sediment or surgical speci- mens could be a useful diagnostic marker and may improve the diagnosis of the bladder cancer. Recently, UHRF1’s overpression has also been described in lung cancer cells, particularly in non-adenocarcinomas [40]. This alteration in UHRF1 expression could be linked to the degree of the lung cancer aggressiveness and was detectable in half of the patients in an early pathological stage. This suggests therefore that UHRF1 could be a novel diagnostic tool for lung cancer [40]. Altogether,