017 | Targeting lipogenesis promotes the synergistic effect of the selective HDAC inhibitor ITF3756 with bortezomib in colon cancer cells

Marzia Franzò¹, Giovanni Pratelli¹, Federica Affranchi², Antonietta Notaro², Michela Giuliano², Sonia Emanuele¹ | ¹Department of Biomedicine, Neuroscience and Advanced Diagnostics, Biochemistry Building, University of Palermo, Italy; ²Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Italy.

Selective inhibition of histone deacetylases (HDACs) has gained increasing attention as a promising strategy for antitumor targeted therapy [1]. HDAC6, a member of the HDAC family, deacetylates non-histone proteins and modulates several cellular processes, including lipid metabolism [2]. HDAC6 is involved in the development and progression of colorectal cancer (CRC) and is associated with poor prognosis. The selective HDAC6 inhibitor ITF3756 reduced the viability of HCT116 and HT29 colon cancer cells while inducing lipid accumulation. Based on the involvement of HDAC6 in lipid metabolism control, ITF3756 was combined with bortezomib (BTZ), a proteasome inhibitor known to promote lipogenesis [3]. At subtoxic doses, the combined treatment of ITF3756 and BTZ exerted a synergistic pro-apoptotic effect in HCT116 cells. Interestingly, the combination enhanced lipid synthesis as shown by Oil Red O staining, which was associated with mTOR phosphorylation, SREBP-1 activation, and increased PPARγ expression. The ITF3756/BTZ combination was less effective in HT29 cells, which exhibited high basal levels of lipid droplets. Inhibition of diacylglycerol acyltransferase 1 (DGAT-1) and 2 (DGAT-2) suppressed lipogenesis and potentiated the effects of the ITF3756/BTZ combination in both cell lines, suggesting that lipid accumulation acts as a protective mechanism. This hypothesis was further supported by SREBP-1 silencing, which also enhanced the antitumor efficacy of the ITF3756/BTZ combination in HCT116 cells. Overall, these findings highlight the promising antitumor activity of the selective HDAC6 inhibitor when combined with BTZ in colon cancer cells and suggest that the combination with anti-lipogenic compounds may represent a nice tool for potential clinical applications.