Bortezomib-Induced Epigenetic Alterations in Nerve Cells: Focus on the Mechanisms Contributing to the Peripheral Neuropathy Development

Abstract

Bortezomib-induced peripheral neuropathy (BiPN) occurs in approximately 40% of patients with multiple myeloma. The induction of severe neuropathy entails the dose reduction or complete elimination of bortezomib (BTZ). Interestingly, discontinuation of BTZ mostly results in a reduction or complete resolution of peripheral neuropathy (PN) symptoms. Therefore, it is likely that the BiPN mechanisms are based on temporary/reversible changes such as epigenetic alterations. In this study, we examined the effect of treating nerve cells, differentiated from the Lund human mesencephalic (dLUHMES) cell line, with several low-dose BTZ (0.15 nM) applications. We showed a significant decrease in global histone H3 acetylation as well as histone H3 lysine 9 acetylation. Moreover, analysis of the genetic microarray showed changes mainly in epigenetic processes related to chromatin rearrangement, chromatin silencing, and gene silencing. GSEA analysis revealed three interesting signaling pathways (SIRT1, B-WICH and, b-Catenin) that may play a pivotal role in PN development. We also performed an analysis of the miRNA microarray which showed the interactions of miR-6810-5p with the genes MSN, FOXM1, TSPAN9, and SLC1A5, which are directly involved in neuroprotective processes, neuronal differentiation, and signal transduction. The study confirmed the existence of BTZ-induced complex epigenetic alterations in nerve cells. However, further studies are necessary to assess the reversibility of epigenetic changes and their potential impact on the induction/resolution of PN.