Alhosin et al. Journal of Experimental & Clinical Cancer Research 2011, 30:41 http://www.jeccr.com/content/30/1/41 Page 5 of 10 Figure 2 Schematic model of the role of UHRF1/DNMT1 complex in the regulation of p16INK4A and VEGF gene expressions. A. When the SRA domain of UHRF1 meets hemi-methylated DNA present in the p16INK4A promoter, UHRF1 acts as a guide for DNMT1 to methylate the complementary DNA strand. Subsequently a p16INK4A gene repression and VEGF gene activation are maintained on the DNA daughter strands, i.e., in the daughter cancer cells. B. The UHRF1 down-regulation, by natural compounds such as TQ or polyphenols, induces the DNMT1 abundance decrease, that is accompanied by a p16INK4A gene re-expression and a down-regulation of VEGF gene expression. and ovarian cancers in women in Asian countries [73]. Black seed (nigella sativia) belongs to the Ranuncula- ceae family which grows in the Mediterranean sea and Western Asia countries, including Pakistan, India and China [74]. This plant is used in traditional folk medi- cine for the prevention and the treatment of numerous diseases such as eczema, cough, bacterial and viral infec- tions, hypertension and diabetes [75]. The chemothera- peutic and chemopreventive activities of black cumin oil are attributed to thymoquinone (TQ). Several in vitro and in vivo studies have shown that TQ has potent cytotoxic and genotoxic activities on a wide range of cancer cells [76-80]. TQ exerts its anti-cancer effects by inhibiting cell proliferation, arresting cell cycle progres- sion and inducing subsequently apoptosis by p53- dependent or -independent pathways. By using the acute lymphoblastic leukemia jurkat cell model (p53 mutated cell line), we have demonstrated that TQ trig- gers apoptosis through the production of reactive oxy- gen species (ROS) and the activation of the p73 gene [67]. This tumor suppressor gene seems to act as a cel- lular gatekeeper by preventing the proliferation of TQ- exposed Jurkat cells [67]. Obviously, the observed p73 activation triggers G1 cell cycle arrest and apoptosis. Interestingly, a transient TQ concentration-dependent up-regulation of caspase 3 cleaved subunits was also observed, suggesting that TQ exerts its apoptotic activity through a p73-dependent caspase-dependent cell death pathway. Consistently with our study, it was recently reported that catechin, a natural polyphenolic com- pound, induces apoptosis, in a similar way as does TQ, by its ability to increase the expression of pro-apoptotic genes such as caspase-3, -8, and -9 and p53 [81]. Inter- estingly, our study also showed that TQ down-regulated UHRF1, DNMT1 and HDAC1 expressions [67]. We determined that p73 was responsible for UHRF1 down- regulation through a caspase-3 dependent process. A subsequent study allowed us to propose that down-regu- lation of phosphodiesterase 1A (PDE1A), a modulator of cAMP and cGMP cyclic nucleotides, could be the key event to explain the TQ-induced down-regulation of UHRF1 and the occurrence of apoptosis [82]. All these findings showed for the first time that a natural com- pound induces apoptosis by acting on the epigenetic integrator UHRF1 through a p73-dependent mitochon- drial pathway.