Oxaliplatin-induced neuropathic pain involvesHOXA6via aTET1-dependent demethylation of theSOX10promoter

Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of cancer treatment but the underlying mechanisms are largely unknown. Here, we used a whole-genome expression microarray and gene ontology analysis to identify the upregulation of a sequence-specific DNA-binding protein, HOXA6, in the spinal dorsal horn on Day 10 after injection of rats with oxaliplatin. Genetic disruption of HOXA6 with siRNAs alleviated mechanical allodynia after oxaliplatin administration. Reduced representation bisulfite sequencing assays indicated that oxaliplatin decreased the methylation levels of theSOX10promoter but not ofHOXA6. TET1 was also upregulated by oxaliplatin. Genetic disruption of TET1 withsiRNAblocked the promoter demethylation ofSOX10and the upregulation of HOXA6 and SOX10. Importantly, inhibition of SOX10 by intrathecal application of SOX10 siRNA ameliorated the mechanical allodynia induced by oxaliplatin and downregulated the expression of HOXA6. Consistently, overexpression of SOX10 through intraspinal injection of AAV-SOX10-EGFP produced mechanical allodynia and upregulated the expression of spinal dorsal horn HOXA6. Moreover, chromatin immunoprecipitation assays demonstrated that oxaliplatin increased the binding of SOX10 to the promoter region ofHOXA6. Taken together, our data suggest that HOXA6 upregulation through the TET1-mediated promoter demethylation ofSOX10may contribute to oxaliplatin-induced neuropathic pain.