Upregulation of TRPC6 Mediated by PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced by Chemotherapeutics in Dorsal Root Ganglion

• Published in: The international journal of neuropsychopharmacology 2020-04, Vol.23 (4), p.257-267
• Main Authors: Zhang, Xiang-Zhong, Luo, De-Xing, Bai, Xiao-Hui, Ding, Huan-Huan, Liu, Meng, Deng, Jie, Mai, Jing-Wen, Yang, Yan-Ling, Zhang, Su-Bo, Ruan, Xiang-Cai, Zhang, Xue-Qin, Xin, Wen-Jun, Xu, Ting
• Format: Article
• Language: English
• Subjects: Animals; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Bortezomib - pharmacology; Cancer; Cancer pain; Carrier proteins; Chemotherapy; Complications and side effects; Development and progression; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferases - drug effects; DNA Methylation - drug effects; DNA Methyltransferase 3B; Dorsal root ganglia; Ganglia, Spinal - drug effects; Gene Expression - drug effects; Genetic aspects; Health aspects; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Male; Neuralgia; Neuralgia - chemically induced; Neuralgia - complications; Oxaliplatin - pharmacology; Paclitaxel - pharmacology; PAX6 Transcription Factor - drug effects; Rats; Rats, Sprague-Dawley; Regular; Transcription factors; TRPC Cation Channels - antagonists & inhibitors; TRPC Cation Channels - drug effects; Up-Regulation - drug effects
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1093/ijnp/pyaa014

Abstract Background Although the action mechanism of antineoplastic agents is different, oxaliplatin, paclitaxel, or bortezomib as first-line antineoplastic drugs can induce painful neuropathy. In rodents, mechanical allodynia is a common phenotype of painful neuropathy for 3 chemotherapeutics. However, whether there is a common molecular involved in the different chemotherapeutics-induced painful peripheral neuropathy remains unclear. Methods Mechanical allodynia was tested by von Frey hairs following i.p. injection of vehicle, oxaliplatin, paclitaxel, or bortezomib in Sprague-Dawley rats. Reduced representation bisulfite sequencing and methylated DNA immunoprecipitation were used to detect the change of DNA methylation. Western blot, quantitative polymerase chain reaction, chromatin immunoprecipitation, and immunohistochemistry were employed to explore the molecular mechanisms. Results In 3 chemotherapeutic models, oxaliplatin, paclitaxel, or bortezomib accordantly upregulated the expression of transient receptor potential cation channel, subfamily C6 (TRPC6) mRNA and protein without affecting the DNA methylation level of TRPC6 gene in DRG. Inhibition of TRPC6 by using TRPC6 siRNA (i.t., 10 consecutive days) relieved mechanical allodynia significantly following application of chemotherapeutics. Furthermore, the downregulated recruitment of DNA methyltransferase 3 beta (DNMT3b) at paired box protein 6 (PAX6) gene led to the hypomethylation of PAX6 gene and increased PAX6 expression. Finally, the increased PAX6 via binding to the TPRC6 promoter contributes to the TRPC6 increase and mechanical allodynia following chemotherapeutics treatment. Conclusions The TRPC6 upregulation through DNMT3b-mediated PAX6 gene hypomethylation participated in mechanical allodynia following application of different chemotherapeutic drugs.