NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin.
Meng LiuJing-Wen MaiDe-Xing LuoGuan-Xi LiuTing XuWen-Jun XinSu-Yan LinZhen-Yu LiPublished in: Molecular pain (2023)
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.
Keyphrases
- neuropathic pain
- spinal cord
- spinal cord injury
- transcription factor
- signaling pathway
- dna methylation
- gene expression
- cell proliferation
- cell death
- high throughput
- poor prognosis
- single cell
- endoplasmic reticulum stress
- genome wide
- high glucose
- combination therapy
- chemotherapy induced
- drug induced
- bioinformatics analysis
- rna seq
- long non coding rna
- smoking cessation