2. Academic Validation
  3. The combinations of histone lysine demethylase inhibitors with panobinostat exert enhanced effects against head and neck cancer cells

The combinations of histone lysine demethylase inhibitors with panobinostat exert enhanced effects against head and neck cancer cells

  • Exp Cell Res. 2026 Jul 1;460(1):115042. doi: 10.1016/j.yexcr.2026.115042.
Dawid Dorna 1,  Robert Kleszcz 2,  Karolina Drabarz 3,  Małgorzata Kubiak 4,  Barbara Stefanska 5,  Jarosław Paluszczak 6
Affiliations

Affiliations

  • 1 Poznan University of Medical Sciences, Doctoral School, Poznań, Poland; Poznan University of Medical Sciences, Department of Pharmaceutical Biochemistry, Poznań, Poland(1); The University of British Columbia, Food, Nutrition and Health Program, Faculty of Land and Food Systems, Vancouver, Canada. Electronic address: [email protected].
  • 2 Poznan University of Medical Sciences, Department of Pharmaceutical Biochemistry, Poznań, Poland(1). Electronic address: [email protected].
  • 3 Poznan University of Medical Sciences, Department of Pharmaceutical Biochemistry, Poznań, Poland(1).
  • 4 Warsaw University of Life Sciences, Center of Cellular Immunotherapies, Warsaw, Poland; The University of British Columbia, Food, Nutrition and Health Program, Faculty of Land and Food Systems, Vancouver, Canada. Electronic address: [email protected].
  • 5 The University of British Columbia, Food, Nutrition and Health Program, Faculty of Land and Food Systems, Vancouver, Canada. Electronic address: [email protected].
  • 6 Poznan University of Medical Sciences, Department of Pharmaceutical Biochemistry, Poznań, Poland(1). Electronic address: [email protected].
PMID: 42019757 DOI: 10.1016/j.yexcr.2026.115042
Abstract

The effectiveness of treatment of head and neck squamous cell carcinomas (HNSCC) is still unsatisfactory, and novel therapeutics could improve outcomes. Histone deacetylases (HDAC) and histone lysine demethylases (KDMs) emerged as important molecular targets in HNSCC. Moreover, joint inhibition of epigenetic targets may be therapeutically advantageous. Thus, the aim of this project was to evaluate the effects of combinations of panobinostat, a pan-HDAC inhibitor, with KDM4-6 inhibitors (KDMi), ML324, GSK-J4, and JIB-04. Experiments were performed in FaDu and SCC-152 cell lines. Resazurin and clonogenic assays were used to evaluate the cell viability and clonogenic potential, respectively. Apoptosis was assessed by flow cytometry after Annexin V staining. Flow-cytometric detection of γH2A.X was applied for DNA damage evaluation. Gene expression was quantified by qPCR. KDM proteins occupancy at gene promoters was measured by quantitative chromatin immunoprecipitation. KDMi enhanced the Anticancer effects of panobinostat in HNSCC cell lines. The combinations of panobinostat with ML324 and JIB-04 synergistically reduced cell viability in FaDu and SCC-152 cells, and increased Apoptosis induction in SCC-152 cells. These effects could be attributed to the modulation of BIRC5 and CDKN2A expression, and enhanced accumulation of DNA double-strand breaks following combinatorial treatments in FaDu cells. Decreased expression of stemness-related genes upon KDMi treatment in FaDu cells was associated with decreased binding of KDM4A and/or KDM6B at SOX2 and POU5F1 gene promoters. The suppression of stemness-associated phenotype, and the concurrent promotion of Apoptosis by the studied combinations of chemicals, suggest their potential as a novel therapeutic strategy in HNSCC.

Keywords

Head and neck cancer; Histone deacetylase; Histone lysine demethylase; JIB-04; ML324; Panobinostat.

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