ZEB1 Induces Ddr1 Promoter Hypermethylation and Contributes to the Chronic Pain in Spinal Cord in Rats Following Oxaliplatin Treatment
ZEB1 Induces Ddr1 Promoter Hypermethylation and Contributes to the Chronic Pain in Spinal Cord in Rats Following Oxaliplatin Treatment
复制标题
ZEB1 诱导 Ddr1 启动子高甲基化并导致奥沙利铂治疗后大鼠脊髓慢性疼痛
DOI：
10.1007/s11064-021-03355-5
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发表时间：
2021-05-25
影响因子：
4.4
通讯作者：
Li, Zhen-Yu
中科院分区：
文献类型：
--
作者：
Chen, Yi-Ying;Jiang, Kai-Sheng;Li, Zhen-Yu
应用化疗药物奥沙利铂通过诱导DNA甲基化抑制基因转录，这可能有助于奥沙利铂诱导的慢性疼痛。在此，在奥沙利铂处理后，从SRA甲基化数据库（PRJNA 587622）中筛选Ddr 1，其显示启动子中甲基化增加。qPCR和MeDIP检测证实奥沙利铂处理后脊髓背角神经元中DDR 1基因启动子区甲基化程度增加，DDR 1表达降低。此外，通过椎管内注射AAV-hSyn-Ddr 1过表达DDR 1显著减轻奥沙利铂诱导的机械性异常性疼痛。此外，我们发现奥沙利铂处理增加了DNMT 3b和ZEB 1在背角神经元中的表达，并促进了DNMT 3b和ZEB 1之间的相互作用。鞘内注射ZEB 1 siRNA可抑制奥沙利铂诱导的DNMT 3b募集增强和Ddr 1启动子的高甲基化。最后，ZEB 1 siRNA挽救了奥沙利铂诱导的DDR 1下调和机械性异常性疼痛。总之，这些结果表明，ZEB 1将DNMT 3b募集到Ddr 1启动子，这诱导了DDR 1下调，并促成了奥沙利铂诱导的慢性疼痛。
Application of chemotherapeutic oxaliplatin represses gene transcription through induction of DNA methylation, which may contribute to oxaliplatin-induced chronic pain. Here, Ddr1, which showed an increased methylation in the promoter, was screened from the SRA methylation database (PRJNA587622) after oxaliplatin treatment. qPCR and MeDIP assays verified that oxaliplatin treatment increased the methylation in Ddr1 promoter region and decreased the expression of DDR1 in the neurons of spinal dorsal horn. In addition, overexpression of DDR1 by intraspinal injection of AAV-hSyn-Ddr1 significantly alleviated the mechanical allodynia induced by oxaliplatin. Furthermore, we found that oxaliplatin treatment increased the expression of DNMT3b and ZEB1 in dorsal horn neurons, and promoted the interaction between DNMT3b and ZEB1. Intrathecal injection of ZEB1 siRNA inhibited the enhanced recruitment of DNMT3b and the hypermethylation in Ddr1 promoter induced by oxaliplatin. Finally, ZEB1 siRNA rescued the DDR1 downregulation and mechanical allodynia induced by oxaliplatin. In conclusion, these results suggested that the ZEB1 recruited DNMT3b to the Ddr1 promoter, which induced the DDR1 downregulation and contributed to the oxaliplatin-induced chronic pain.