Abstract
BackgroundEpigenetic control using histone deacetylase (HDAC) inhibitors is a promising therapy for lymphomas. Insights into the anti-proliferative effects of HDAC inhibitors on diffuse large B-cell lymphoma (DLBCL) and further understanding of the underlying mechanisms, which remain unclear to date, are of great importance.MethodsThree DLBCL cell lines (DoHH2, LY1 and LY8) were used to define the potential epigenetic targets for Trichostatin A (TSA)-mediated anti-proliferative effects via CCK-8 assay. Cell cycle distribution and apoptosis were detected by flow cytometry. We further investigated the underlying molecular mechanisms by examining expression levels of relevant proteins using western blot analysis.ResultsTSA treatment inhibited the growth of all three DLBCL cell lines and enhanced cell cycle arrest and apoptosis. Molecular analysis revealed upregulated acetylation of histone H3, α-tubulin and p53, and dephosphorylation of pAkt with altered expression of its main downstream effectors (p21, p27, cyclin D1 and Bcl-2). HDAC profiling revealed that all three cell lines had varying HDAC1–6 expression levels, with the highest expression of all six isoforms, in DoHH2 cells, which displayed the highest sensitivity to TSA.ConclusionOur results demonstrated that the HDAC inhibitor TSA inhibited DLBCL cell growth, and that cell lines with higher expression of HDACs tended to be more sensitive to TSA. Our data also suggested that inhibition of pAkt and activation of p53 pathway are the main molecular events involved in inhibitory effects of TSA.
Highlights
Epigenetic control using histone deacetylase (HDAC) inhibitors is a promising therapy for lymphomas
After 48 h treatment, the relative cell viability of DoHH2, LY1 and LY8 cells declined to 40%, 60% and 41%, respectively, and declined further to 21%, 19% and 6% after 72 h treatment, indicating that Trichostatin A (TSA) exhibits its inhibitory effects in diffuse large B-cell lymphoma (DLBCL) cells in a time-dependent manner (Figure 1C, D)
TSA suppressed the growth of all three DLBCL cell lines by enhanced G0/G1 or G2/M arrest and possible apoptosis
Summary
Epigenetic control using histone deacetylase (HDAC) inhibitors is a promising therapy for lymphomas. Insights into the anti-proliferative effects of HDAC inhibitors on diffuse large B-cell lymphoma (DLBCL) and further understanding of the underlying mechanisms, which remain unclear to date, are of great importance. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma. The histone deacetylase (HDAC) enzymes remove acetyl groups from histone and non-histone proteins, and lead to the formation of a compacted and transcriptionallyrepressed chromatin structure. Class 1 and 2 histone deacetylase expression in a panel of lymphoma cell lines and tissue sections was previously reported [3], and clinical evaluation indicates that lymphoid malignancies are more sensitive to HDAC inhibitors compared to other solid tumors [4]. HDAC inhibitors, e.g. Romidepsin (Istodax, Celgene, Summit, USA) and Vorinostat (Zolinza, Merck, Whitehouse Station, USA), have been accepted by the US FDA for treating advanced and refractory cutaneous T-cell lymphoma (CTCL) [6]
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