Alhosin et al. Journal of Experimental & Clinical Cancer Research 2011, 30:41 http://www.jeccr.com/content/30/1/41 Page 4 of 10 an increase in Tip60 expression, which was associated with a decrease of acetylated H2AK5, suggesting that Tip60 requires UHRF1 for H2AK5 acetylation [54]. This mark could be involved in the epigenetic silencing of TSGs, but this possibility requires further investigations. The other studies reported that through an acetylation- dependent process UHRF1/Tip60 acts as destroyers of DNMT1 whereas HDAC1/HAUSP act as protectors for DNMT1 [55-57]. The paradigm resulting from this study additionally supports the idea of the existence of a macromolecular complex involved in the duplication of the epigenetic code that is capable of self regulation through external signals [57]. This complex is able to duplicate the epigenetic code after DNA replication and thus, allows cancer cells to maintain the repression of TSGs, including for instance BRCA1 and p16INK4A [49,58]. Indeed, it has been reported that UHRF1 is responsible for the repression of BRCA1 gene in spora- dic breast cancer through DNA methylation, by recruit- ing DNMT1, and histone deacetylation or methylation, by recruiting HDAC1, or G9a, respectively [58]. As a platform protein, UHRF1 is expected to be the major conductor of the epigenetic orchestra by using various executors to facilitate the conservation of the silencing marks, especially those concerning TSGs repression in the cancer cells. Thus, targeting this epigenetic conduc- tor may be a new promising approach for anticancer therapy. Until today, only the two key partners of UHRF1 (DNMT1 and HDAC1) are targeted therapeutically. Indeed, two large families of specific inhibitors of DNMT1 (DNMTi) and HDAC1 (HDACi) are commer- cially available but which efficiency in solid tumors is often questioned [59,60]. The current challenge is there- fore to find new targets which will enable to treat more efficiently cancer, with lower toxicity and more specifi- city to reduce the side effects of these chemical com- pounds. Considering that DNMT1 and probably HDAC1 require UHRF1 to fully exert their effects, inhi- biting the UHRF1 activity or expression would theoreti- cally mimic the cumulative effects of HDAC1 and DNMT1 inhibitors and thus would be highly efficient, especially in solid tumors in which DNMTs are particu- larly less active. 4. Targeting UHRF1 abundance by natural compounds Targeting UHRF1 abundance and/or UHRF1’s enzy- matic activity would have application in several types of cancer. UHRF1 is essential for cell proliferation and therefore, to our opinion it would be more rational to target cancer types in which UHRF1 is actually found in high abundance, i.e., over-expressed. UHRF1 has been reported to be over-expressed in various cancers such as breast, bladder, kidney, lung, prostate, cervical, and pancreatic cancers, as well as in astrocytomas and glio- blastoma [35,40,61]. The anticancer strategic idea would be not to completely inhibit UHRF1 expression consid- ering that UHRF1 is also necessary for non cancerous to proliferate [44,62,63], hence, for instance, for physiologic tissue regeneration. Thus, to consolidate the anti- UHRF1 therapeutic interest, it would be interesting to show that diminishing but not abolishing UHRF1’s expression by chronic treatment of natural compound is sufficient for re-expression of silenced tumor suppressor genes. An ideal property for future natural compounds as anti-cancer drugs, would be that cancer cells but not normal cells are affected by them in order to undergo apoptosis via an UHRF1 down-regulation. Targeting UHRF1 is particularly interesting because this protein regulates the G1/S transition [47-49,62,63]. The arrest at G1/S checkpoint is mediated by the action of the tumor suppressor gene p53 or its functional homologue p73 [64,65]. Recent years have seen a dramatic progress in understanding mechanisms that regulate the cell divi- sion. In this context, we and other groups have shown that UHRF1 is essential for G1/S transition [63]. Loss of p53 activity, as a result of genetic mutations or epige- netic alterations in cancer, prevents G1/S checkpoints. DNA damage induces a p53 or p73 up-regulation (in p53-deficient cells) that activates the expression of p21cip/waf or p16INK4A, resulting in cell cycle arrest at G1/S transition [65,66]. We have shown that UHRF1 represses the expression of tumour suppressor genes such as p16INK4A &RB1 leading to a down-regulation of the Vascular Endothelial Growth Factor (VEGF, Figure 2A) [49] and by a feedback mechanism, UHRF1 may be regulated by other tumour suppressor genes such as p53 and p73 products [46,67]. This suggests that the appear- ance of genetic and/or epigenetic abnormalities of TSGs including p53 and p73 genes, in various human cancers would be an explanation for the observed UHRF1 over- expression. Since UHRF1 controls the duplication of the epigenetic code after DNA replication, the inability of p53 and P73 to down-regulate UHRF1, allows the daughter cancer cells to maintain the repression of tumour suppressor genes observed in the mother cancer cell [26,68]. Over the last millenium, herbal products have been commonly used for prevention and treatment of various diseases including cancer [69-71]. One of these natural products is curcumin which has potent anti-cancer properties in experimental systems. Curcumin is con- sumed in high quantities in Asian countries and epide- miological studies have attributed the lower rate of colon cancer in these countries to its consumption [72]. Green tea is also widely consumed in Asia countries. This natural product, which is rich in polyphenols, has been shown to significantly decrease the risk of breast