OncoTargets and Therapy (Jun 2020)

HDAC1/2 Inhibitor Romidepsin Suppresses DEN-Induced Hepatocellular Carcinogenesis in Mice

  • Afaloniati H,
  • Angelopoulou K,
  • Giakoustidis A,
  • Hardas A,
  • Pseftogas A,
  • Makedou K,
  • Gargavanis A,
  • Goulopoulos T,
  • Iliadis S,
  • Papadopoulos V,
  • Papalois A,
  • Mosialos G,
  • Poutahidis T,
  • Giakoustidis D

Journal volume & issue
Vol. Volume 13
pp. 5575 – 5588

Abstract

Read online

Hara Afaloniati,1 Katerina Angelopoulou,1 Alexander Giakoustidis,2 Alexandros Hardas,3 Athanasios Pseftogas,4 Kali Makedou,5 Athanasios Gargavanis,2 Thomas Goulopoulos,2 Stavros Iliadis,5 Vasileios Papadopoulos,2 Apostolos Papalois,6 George Mosialos,4 Theofilos Poutahidis,3 Dimitrios Giakoustidis2 1Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2First Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece; 3Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece; 4School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece; 5Department of Biological Chemistry, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece; 6Experimental, Educational and Research Center, ELPEN, Pikermi, Attica, GreeceCorrespondence: Dimitrios GiakoustidisFirst Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, GreeceTel +30 6932306133Email [email protected]: Hepatocellular carcinoma (HCC) is a frequently diagnosed cancer and a leading cause of cancer-related death worldwide. Its rapid progression, combined with the limited treatment options at late stages, imposes the need for early detection and aggressive intervention. Based on the knowledge that hepatocarcinogenesis is significantly influenced by histone acetylation, we directed our search for novel HCC therapeutics among histone deacetylation inhibitors (HDACi). The aim of the present study was to investigate the effect of HDAC1/2 inhibitor Romidepsin in the well-established mouse model of diethylnitrosamine (DEN)-induced HCC.Materials and Methods: C56BL/6 mice were treated with Romidepsin at the critical point of 10 months after DEN challenge and their livers were examined 2 months later using histopathology and morphometry. Protein levels were assessed in serum using ELISA and in liver tissues using Western blot and immunohistochemistry (in-situ detection). Gene expression was quantified using real-time PCR.Results: Romidepsin suppressed cancer progression. This effect was associated with decreased proliferation and increased apoptosis of cancer cells. The cell cycle regulator CK2a, the anti-inflammatory molecule PPAR-γ, and the tumor suppressors PTEN and CYLD were upregulated in treated HCC. By contrast, the expression of PI3K, NF-κB p65 and c-Jun was reduced. In line with this result, the levels of two major apoptosis regulators, ie, BAD and the multifunctional protein c-Met, were lower in the blood serum of treated mice compared to the untreated mice with HCC.Conclusion: These findings suggest that Romidepsin, a drug currently used in the treatment of lymphoma, could also be considered in the management of early-stage HCC.Keywords: diethylnitrosamine, DEN, histone deacetylases, HDAC, HDAC inhibitors, HDACi, hepatocellular carcinoma, HCC, Romidepsin

Keywords