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Upregulation of TRPC6 Mediated by PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced by Chemotherapeutics in Dorsal Root Ganglion.
Int J Neuropsychopharmacol. 2020 04 23; 23(4):257-267.IJ

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.

Authors+Show Affiliations

The Third Affiliated Hospital, Sun Yet-Sen University, Guangzhou, Guangdong, China.Department of Anesthesiology, Huizhou Central People's Hospital, Huizhou, Guangdong, China.Department of Anesthesiology, Sun Yat-sen Memorial Hospital Guangzhou, China.Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease Sun Yat-Sen University, Guangzhou, China.Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease Sun Yat-Sen University, Guangzhou, China.Department of Anesthesia and Pain Medicine, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.Department of Anesthesiology, Huizhou Central People's Hospital, Huizhou, Guangdong, China.The Third Affiliated Hospital, Sun Yet-Sen University, Guangzhou, Guangdong, China.Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Rehabilitation Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.Department of Anesthesia and Pain Medicine, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China.Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease Sun Yat-Sen University, Guangzhou, China.Zhongshan School of Medicine, Guangdong Province Key Laboratory of Brain Function and Disease Sun Yat-Sen University, Guangzhou, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32124922

Citation

Zhang, Xiang-Zhong, et al. "Upregulation of TRPC6 Mediated By PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced By Chemotherapeutics in Dorsal Root Ganglion." The International Journal of Neuropsychopharmacology, vol. 23, no. 4, 2020, pp. 257-267.
Zhang XZ, Luo DX, Bai XH, et al. Upregulation of TRPC6 Mediated by PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced by Chemotherapeutics in Dorsal Root Ganglion. Int J Neuropsychopharmacol. 2020;23(4):257-267.
Zhang, X. Z., Luo, D. X., Bai, X. H., Ding, H. H., Liu, M., Deng, J., Mai, J. W., Yang, Y. L., Zhang, S. B., Ruan, X. C., Zhang, X. Q., Xin, W. J., & Xu, T. (2020). Upregulation of TRPC6 Mediated by PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced by Chemotherapeutics in Dorsal Root Ganglion. The International Journal of Neuropsychopharmacology, 23(4), 257-267. https://doi.org/10.1093/ijnp/pyaa014
Zhang XZ, et al. Upregulation of TRPC6 Mediated By PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced By Chemotherapeutics in Dorsal Root Ganglion. Int J Neuropsychopharmacol. 2020 04 23;23(4):257-267. PubMed PMID: 32124922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Upregulation of TRPC6 Mediated by PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced by Chemotherapeutics in Dorsal Root Ganglion. AU - Zhang,Xiang-Zhong, AU - Luo,De-Xing, AU - Bai,Xiao-Hui, AU - Ding,Huan-Huan, AU - Liu,Meng, AU - Deng,Jie, AU - Mai,Jing-Wen, AU - Yang,Yan-Ling, AU - Zhang,Su-Bo, AU - Ruan,Xiang-Cai, AU - Zhang,Xue-Qin, AU - Xin,Wen-Jun, AU - Xu,Ting, PY - 2019/10/24/received PY - 2020/02/01/revised PY - 2020/02/25/accepted PY - 2020/3/4/pubmed PY - 2021/5/20/medline PY - 2020/3/4/entrez KW - Chemotherapeutics KW - DNA methylation KW - PAX6 KW - TRPC6 KW - mechanical allodynia SP - 257 EP - 267 JF - The international journal of neuropsychopharmacology JO - Int J Neuropsychopharmacol VL - 23 IS - 4 N2 - 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. SN - 1469-5111 UR - https://www.unboundmedicine.com/medline/citation/32124922/Upregulation_of_TRPC6_Mediated_by_PAX6_Hypomethylation_Is_Involved_in_the_Mechanical_Allodynia_Induced_by_Chemotherapeutics_in_Dorsal_Root_Ganglion_ L2 - https://academic.oup.com/ijnp/article-lookup/doi/10.1093/ijnp/pyaa014 DB - PRIME DP - Unbound Medicine ER -