Long-Term Treatment with Bortezomib Induces Specific Methylation Changes in Differentiated Neuronal Cells

Abstract

Bortezomib (BTZ) is proteasome inhibitor, effectively used in the treatment of multiple myeloma, but frequently discontinued due to peripheral neuropathy, which develops in patients after consecutive treatment cycles. The molecular mechanisms affected by BTZ in neuronal cells, which result in neuropathy, remain unknown. However, BTZ is unlikely to lead to permanent morphological nerve damage, because neuropathy reverses after discontinuation of treatment, and nerve cells have very limited renewal capacity. We have previously shown that BTZ induces methylation changes in SH-SY5Y cells, which take part in the development of treatment resistance. Here, we hypothesized that BTZ affects the methylomes of mature neurons, and these changes are associated with BTZ neurotoxicity. Thus, we studied methylomes of neuronal cells, differentiated from the LUHMES cell line, after cycles of treatment with BTZ. Our results show that BTZ induces specific methylation changes in mature neurons, which are not present in SH-SY5Y cells after BTZ treatment. These changes appear to affect genes involved in morphogenesis, neurogenesis, and neurotransmission. Furthermore, identified methylation changes are significantly enriched within binding sites of transcription factors previously linked to neuron physiology, including EBF, PAX, DLX, LHX, and HNF family members. Altogether, our results indicate that methylation changes are likely to be involved in BTZ neurotoxicity.

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action

“…Moreover, the identified methylation changes are significantly enriched within the binding sites of transcription factors, including EBF, PAX, DLX, LHX, and HNF family members. The study concluded that alterations in the methylome are likely to be involved in BTZ-mediated neurotoxicity [ 44 ].…”

“…The aim of this review is to provide greater insight into the epigenetic alterations induced by proteasome inhibitors, with particular emphasis on BTZ and its implications in the mechanism of action, the pathophysiology of adverse events, the development of resistance, and clinical implications. We decided to focus on BTZ as we have already investigated BTZ-resistance mechanisms and the role of epigenetic mechanisms in dodging BTZ-induced cytotoxicity [ 43 , 44 , 45 , 46 ]. Furthermore, it remains the most widely utilized proteasome inhibitor globally.…”