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

• Published in: Molecular pain 2023-01, Vol.19, p.17448069231158289
• Main Authors: Liu, Meng, Mai, Jing-Wen, Luo, De-Xing, Liu, Guan-Xi, Xu, Ting, Xin, Wen-Jun, Lin, Su-Yan, Li, Zhen-Yu
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Autophagy; Beclin-1 - genetics; Beclin-1 - metabolism; Beclin-1 - pharmacology; Bioinformatics; Chemotherapy; Chromatin; Disease Models, Animal; DNA methylation; Dorsal horn; Down-regulation; Down-Regulation - genetics; Epigenesis, Genetic; Epigenetics; Histone H4; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - genetics; Immunoprecipitation; Neuralgia; Neuralgia - chemically induced; Neuralgia - drug therapy; Neuralgia - genetics; Oxaliplatin; Pain perception; Rapamycin; Rats; Rats, Sprague-Dawley; Spinal Cord Dorsal Horn - metabolism; Transcription Factors - metabolism; Tuberous sclerosis; Tuberous Sclerosis - metabolism; Tuberous Sclerosis Complex 2
• ISSN: 1744-8069; 1744-8069
• DOI: 10.1177/17448069231158289

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. Graphical Abstract