DNA Methyl-Transferase inhibitors and Histone De-Acetylases inhibitors contrast leukemias reactivating the same apoptosis pathways

The connection between Epigenetic and Cancer is, nowadays, clear: aberrant DNA methylation and/or aberrant histone modifications are associated with a high number of different cancers. For instance, aberrant epigenetic modulations are constantly found in APL, as a consequence of PML/RAR altered recruitment of HDACs and DNMTs. For this reason Epigenetic Drugs are being investigated in both basic and clinic research. HDAC inhibitors and DNMTs inhibitors have been investigated as single drugs, while common features and potentials have been only superficially described. Our work sought to validate Epigenetic Drugs as a new family of anti-cancer agents, using leukemias as a model. We demonstrated that 5’aza 2’-deoxycytidine (DAC), a DNMT inhibitor in vivo prolongs survival in APL mice (as well as AML mice) by reactivating a silent Apoptosis Extrinsic Pathway through the reexpression of TRAIL/APO2L. It is known that the same gene is reactivated also by a HDAC inhibitor, VPA, in the same leukemia models, supporting the hypothesis that drugs targeting different epigenetic modulators can act on the same mechanisms. We also described a hypermethylated region of TRAIL promoter that can be suggested as the direct link between DAC epigenetic modulation and TRAIL re-expression, since CpGs are demethylated and histone H3 acetylation gets significantly increased in this region after drug in vitro treatment. Moreover both VPA and DAC positively cooperated with All Trans Retinoic Acid (ATRA) in contrasting leukemia after ATRA treatment suspension, suggesting that both HDACi and DNMTi can be candidate secondary drugs in differentiating therapies, again having comparable potentials even if acting on different epigenetic targets. We concluded that HDACs and DNMTs are viable new anti-cancer targets, and that drugs acting on them can be considered as one Family of Drugs, with similar properties and potentials.