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ORIGINAL RESEARCH article

Front. Pharmacol.

Sec. Pharmacology of Anti-Cancer Drugs

Targeting lipogenesis promotes the synergistic effect of the selective HDAC6 inhibitor ITF3756 with bortezomib in colon cancer cells

Provisionally accepted
Marzia FranzòMarzia Franzò1Chiara ZichittellaChiara Zichittella1Diana Di LibertoDiana Di Liberto1Giovanni PratelliGiovanni Pratelli1Federica AffranchiFederica Affranchi2Antonietta NotaroAntonietta Notaro2Michela GiulianoMichela Giuliano2Sonia EmanueleSonia Emanuele1,3*
  • 1Universita degli Studi di Palermo Dipartimento di Biomedicina Neuroscienze e Diagnostica avanzata, Palermo, Italy
  • 2Universita degli Studi di Palermo Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Palermo, Italy
  • 3University of Palermo, Palermo, Italy

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Selective histone deacetylase (HDAC) inhibition has recently emerged as a promising strategy for antitumor targeted therapy. HDAC6 is a member of the HDAC family that mainly deacetylates non-histone proteins, regulating multiple cellular functions, including lipogenesis. HDAC6 is associated with the development and progression of colorectal cancer (CRC) and related to CRC poor prognosis. Here we show that the selective HDAC6 inhibitor ITF3756 reduces the viability of HCT116 and HT29 colon cancer cells and promotes lipogenesis. Considering the involvement of HDAC6 in controlling lipid metabolism, ITF3756 was combined with bortezomib (BTZ), a proteasome inhibitor that promotes lipid accumulation. Subtoxic doses of ITF3756 and BTZ exerted a synergistic apoptotic effect in HCT116 cells and caused mTOR phosphorylation, SREBP activation and PPAR increase, thus enhancing lipid production. The ITF3756/BTZ combination was less efficacious in HT29 cells that displayed a high basal level of lipid droplets. Diacylglycerol acyltransferase 1 (DGAT-1) and 2 (DGAT-2) inhibitors blocked lipogenesis and increased the effect of the ITF3756/BTZ combination in both cell lines, thereby suggesting that lipogenesis represents a defensive response. This hypothesis was confirmed by SREBP-1 silencing, which also potentiated the antitumor efficacy of the ITF3756/BTZ combination in HCT116 cells. Overall, these results reveal a particular antitumor efficacy of the selective HDAC6 inhibitor in combination with BTZ in colon cancer cells and suggest that inhibiting lipogenesis is a useful tool to further increase the synergistic effectiveness.

Keywords: HDAC6 inhibitor (HDAC6i), bortezomib (BTZ), Lipid Metabolism, SREBP-1, Apoptosis, colorectal cancer (CRC)

Received: 16 Sep 2025; Accepted: 28 Nov 2025.

Copyright: © 2025 Franzò, Zichittella, Di Liberto, Pratelli, Affranchi, Notaro, Giuliano and Emanuele. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Sonia Emanuele

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material