NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin

Abstract

Neuropathic pain is a common dose-limiting side effect of oxaliplatin, which hampers the effective treatment of tumors. Here, we found that upregulation of transcription factor NFATc2 decreased the expression of Beclin-1, a critical molecule in autophagy, in the spinal dorsal horn, and contributed to neuropathic pain following oxaliplatin treatment. Meanwhile, manipulating autophagy levels by intrathecal injection of rapamycin (RAPA) or 3-methyladenine (3-MA) differentially altered mechanical allodynia in oxaliplatin-treated or naïve rats. Utilizing chromatin immunoprecipitation-sequencing (ChIP-seq) assay combined with bioinformatics analysis, we found that NFATc2 negatively regulated the transcription of tuberous sclerosis complex protein 2 (TSC2), which contributed to the oxaliplatin-induced Beclin-1 downregulation. Further assays revealed that NFATc2 regulated histone H4 acetylation and methylation in the TSC2 promoter site 1 in rats’ dorsal horns with oxaliplatin treatment. These results suggested that NFATc2 mediated the epigenetic downregulation of the TSC2/Beclin-1 autophagy pathway and contributed to oxaliplatin-induced mechanical allodynia, which provided a new therapeutic insight for chemotherapy-induced neuropathic pain.

The Epigenetics of Neuropathic Pain: A Systematic Update

“…All these changes were reversed by metformin, an AMPK activator. Beclin-I downregulation in the dorsal horn also contributes to oxaliplatin-induced neuropathic mechanical allodynia, which involves upregulation of the transcription factor nuclear factor of activated T cells type 2 (NFATc2) in the rat spinal dorsal horn [107]. NFATc2 reduced the expression of the autophagy-related factor tuberous sclerosis complex protein 2 (TSC2) by enhanced H4 methylation at the promoter of the TSC2 gene, with consequent reduction of H4 acetylation.…”