Histone deacetylase inhibitors in plasma cell leukemia treatment: effect of bone marrow microenvironment

Abstract

In the presented study we analysed the effect of histone deacetylase inhibitors (HDACi) suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) on human plasma cell leukemia (PCL) cell line UHKT-944 in the presence of bone marrow microenvironment (BMM). For the analysis, the cells were cultured alone, with bone marrow stromal cells (BMSCs), with extracellular matrix (ECM) components or with interleukin-6, and treated with varied concentrations of SAHA and VPA for 24/48 hours. To study the effect of HDACi, we investigated cell proliferation, apoptosis, cell cycle and changes in selected signalling pathways. We found that both SAHA and VPA induced apoptosis, but had no effect on the cell cycle distribution of UHKT-944 cells. Investigation of the antiproliferative effect of SAHA and VPA revealed that BMSCs and high concentration of interleukin-6 had partial protective effect against SAHA or both inhibitors, respectively. No effect of ECM components on the efficiency of HDACi was observed. We further revealed that VPA down-regulated STAT3 phosphorylation while both inhibitors decreased Akt phosphorylation. In conclusion, VPA and SAHA might represent an additional therapeutic strategy in the PCL treatment. Protective effect of BMM should be taken into account when investigating prospective therapeutic agents against plasma cell disorders.

Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development

“…14 In addition, several studies have shown that HATs and HDACs also (de) acetylate non-histone proteins such as transcription factors, which play an important role in hematopoietic differentiation. [15][16][17][18][19][20][21][22] Given the transcriptional changes associated with neoplastic growth, the use of "epigenetic drugs" has dramatically increased as (adjuvant) treatment of (hematological) malignancies. These drugs include HDAC inhibitors (HDACi) which induce a variety of cellular consequences, including apoptosis, cell cycle arrest, differentiation, and autophagy.…”

“…This epigenomic modification associates with active regulatory DNA and may influence gene expression by chromatin remodeling and the subsequent recruitment of transcriptional regulators 14 . In addition, several studies have shown that HATs and HDACs also (de)acetylate non‐histone proteins such as transcription factors, which play an important role in hematopoietic differentiation 15–22 …”

Coptis Chinensis affects the function of glioma cells through the down-regulation of phosphorylation of STAT3 by reducing HDAC3

“…Phosphorylation and acetylation are key forms of post-translational modification that regulate the active sites of many proteins [ 5 ]. Some reports have demonstrated that VPA plays an important role in regulating the function of STAT3 by reducing the STAT3 phosphorylation level in biological processes [ 23 – 25 ]. Unlike the transient STAT3 phosphorylation in normal cells, sustained activation of STAT3 was observed in 70% of blood and solid tumors and showed the strong dependence, which makes it an ideal drug target [ 26 , 27 ].…”