Modulation of the histone acetylation in Merkel cell carcinoma cells by histone deacetylase inhibitors

Histone acetylation regulates the expression of genes involved in multiple pathways, such as cell proliferation, apoptosis, and immunogenicity. Histone acetylation dysregulation leads to cancer onset, while an antineoplastic activity of histone deacetylase inhibitors, such as panobinostat has been proved in carcinoma. The involvement of dysregulated histone acetylation on the onset of Merkel cell carcinoma (MCC), a rare but aggressive and immunogenic viral induced-skin tumor in 80% of cases, is yet unexplored. We investigated the impact of the histone deacetylase inhibitor panobinostat in modulating the acetylation of histone H3 in Merkel cell polyomavirus (MCPyV) -positive/-negative MCC cells, upon tumor cell phenotype and immunogenicity. Panobinostat -treated MCC cells were investigated for (i) cell proliferation, migration, colony forming potential and apoptosis; (ii) acetylation (ac) of H3 lysines 9, 14, 18 and 27 (H3K9/14/18/27); (iii) mRNA expression of antigen presenting machinery genes HLA-A, MICA and MICB. Panobinostat reduced the MCC cell proliferation, migration and colony forming potential. A significant expression of pro -apoptotic genes in panobinostat-treated MCC cells compared to untreated cells was analyzed. No phenotypic/molecular effects were found in panobinostat-treated fibroblast control cells. H3K9ac and H3K27ac were found in all panobinostat-treated MCC cells. H3K14ac and H3K18ac were undetectable in virus-negative MCC13 and MCC26 cells, while a strong expression was found in treated virus-positive WaGa and PeTa cells. Panobinostat treatment induced the expression of HLAA, MICA and MICB genes in MCC cells. The chromatin remodeling via panobinostat -induced histone acetylation modulation could drive MCC cells towards a reduced cell proliferat ion and immunogenicity, while favoring apoptosis.