THE HDAC INHIBITOR ITF2357 (GIVINOSTAT) AS A KEY PLAYER IN EPIGENETIC TARGETING OF MELANOMA AND COLON CANCER CELLS

Histone deacetylase inhibitors (HDACIs) are epigenetic compounds that have been recently considered for their promising anti-tumor activity. The aim of this PhD thesis was to elucidate and characterize the anti-tumor effect of the HDAC inhibitor ITF2357 (Givinostat) in melanoma and colon cancer cells that are characterized by oncogenic BRAF mutations. Interestingly, data reported in this thesis demonstrate that ITF2357 exerts a remarkable anti-tumor effect in melanoma cells by inducing a switch from a pro-survival autophagy to caspase-dependent apoptosis. The thesis provides the first evidences that ITF2357 is able to target oncogenic BRAF and oncogenic p53. The ITF2357 decreasing effect on BRAF was due to both reduced expression and increased proteolysis, while the effect on p53 was mainly due to proteasome-mediated degradation. Moreover, the thesis demonstrates for the first time an interplay between oncogenic BRAF and oncogenic p53 in melanoma cells, which is reduced by ITF2357, thus supporting a possible use of this compound in melanoma targeted therapy. The anti-tumor effect of ITF2357 was also evaluated in colon cancer cells. In these models, the HDAC inhibitor was combined with other epigenetic drugs, including DNA methyltransferase (DNMT) inhibitors. The results indicated that ITF2357 potentiates the effects of both general and selective DNMT inhibitors in HCT116 cells. Furthermore, the compound was able to increase the immunogenic response induced by these other epi-drugs. Taken together, the results shown in this thesis pave the way for a possible use of ITF2357 for anti-tumor targeted therapy, either alone or in combination with other epigenetic compounds.