NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

• Published in: Journal of neuroinflammation 2020-10, Vol.17 (1), p.1-310, Article 310
• Main Authors: Liu, Meng, Zhang, Su-Bo, Luo, Yu-Xuan, Yang, Yan-Ling, Zhang, Xiang-Zhong, Li, Bo, Meng, Yan, Chen, Yuan-Jie, Guo, Rui-Xian, Xiong, Yuan-Chang, Xin, Wen-Jun, Li, Dai
• Format: Article
• Language: English
• Subjects: Acetylation; Antibodies; Catheters; Chemokines; Chromatin; Chronic pain; Complications and side effects; CXCL14; Cytokines; Development and progression; DNA microarrays; Dorsal horn; Drug dosages; Drug withdrawal; Epigenetic inheritance; Epigenetics; Gene expression; Genetic aspects; Health aspects; Histone acetylation; Histone H4; Immunoprecipitation; Molecular modelling; Nervous system; Neuralgia; Neurological research; Neuropathic pain; Neuropathy; NFATc2; Paclitaxel; Pain; Pain perception; Proteins; siRNA; Solid tumors; Spinal cord; Toxicity; Transcription factors; Up-regulation; Western blotting
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-020-01992-1

Background The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism. Results We found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain. Keywords: Paclitaxel, NFATc2, CXCL14, Histone acetylation, Neuropathic pain