Combination of HDACs and DNMT1 inhibitors exhibits synergic anti-neoplasic effect for different types of cancer [100–103]. A phase I pilot study showed that chronic intake of black raspberries by patients suffering from colorectal cancers leads to down-regulation of DNMT1 and Anlotinib solubility dmso re-expression of TSGs through a DNA demethylating process [104]. This suggests that a therapeutically-induced inhibition A-1210477 ic50 of UHRF1 activity or expression could prevent the action of its preferred partners, HDAC1 and DNMT1, leading to a re-expression of the tumour suppressor genes p16 INK4A and thus allowing the cancer

cells to undergo apoptosis. Conclusion Natural compounds such as TQ, RWPs and potentially others (Figure 4) are triggering IWR-1 a series of events that involve cell cycle arrest, apoptosis and inhibition of angiogenesis, all under the control of UHRF1. UHRF1 is a key component of a macro-molecular complex including among others HDAC1, DNMT1, Tip60 and HAUSP, responsible for the epigenetic code duplication after DNA replication. UHRF1 behaves as a conductor in this replication by performing a crosstalk between DNA methylation and histone modifications. This allows cancer cells to maintain their pathologic repression of TSGs during cell proliferation. This review supports the paradigm that UHRF1 is a potential target for cancer prevention and therapy, since

its repression may lead to the re-expression of TSGs, allowing cancer cells to undergo apoptosis. Natural anticancer products have been shown to suppress the expression of UHRF1. This suggests that these chemo-preventive and chemotherapeutic compounds potentially have the virtues to repair the “”wrong”" epigenetic code in cancer cells by targeting the epigenetic integrator UHRF1. It is very legitimate to propose that down-regulation of UHRF1 by natural compounds is a key event in their mechanism of action, considering that re-expression of tumor suppressor genes in cancer cells is dependent upon demethylation Protein tyrosine phosphatase of their promoters and that UHRF1 is involved in the maintenance of DNA methylation patterns. These studies also highlight that UHRF1 and its partners are putative targets for the adaptation to environmental factors, such

as diet. We also do not exclude that the behavior of the epigenetic code replication machinery, ECREM, might influence transgenerational message of environmental factors. Figure 4 Summary of the effects of natural products such as TQ and RWPs. These compounds are putative “”regulators”" of the epigenetic code inheritance, since they are able to target UHRF1 with a subsequent cell cycle arrest, apoptosis and tumor vascularization reduction. An open square containing a question mark, emphases the possibility that numerous other natural compounds can take the same pathways leading to apoptosis. References 1. Weiderpass E: Lifestyle and cancer risk. J Prev Med Public Health 2010, 43:459–471.PubMedCrossRef 2. Jones PA, Laird PW: Cancer epigenetics comes of age.