We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Oxaliplatin‐induced neuropathic pain involves HOXA6 via a TET1‐dependent demethylation of the SOX10 promoter.
- Authors
Deng, Jie; Ding, Huan‐Huan; Long, Jia‐Li; Lin, Su‐Yan; Liu, Meng; Zhang, Xue‐Qin; Xin, Wen‐Jun; Ruan, Xiangcai
- Abstract
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 the SOX10 promoter but not of HOXA6. TET1 was also upregulated by oxaliplatin. Genetic disruption of TET1 with siRNA blocked the promoter demethylation of SOX10 and 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 of HOXA6. Taken together, our data suggest that HOXA6 upregulation through the TET1‐mediated promoter demethylation of SOX10 may contribute to oxaliplatin‐induced neuropathic pain. What's new? Neuropathic pain severely limits the use of oxaliplatin in cancer therapy, for reasons not fully understood. A possible mechanism underlying this phenomenon is the formation of platinum‐DNA crosslinks. This study describes a role for upregulation of the DNA‐binding protein HOXA6 in oxaliplatin‐induced neurotoxicity. In oxaliplatin‐treated rats, neuropathic pain was alleviated upon HOXA6 genetic disruption. TET1‐dependent demethylation of the SOX10 promoter was found to mediate HOXA6 upregulation. Based on previous studies in which HOXA6 downregulation exerted inhibitory effects in colorectal cancer, the present findings indicate that disruption of HOXA6 expression may ameliorate oxaliplatin‐induced neuropathic pain while also blocking tumor growth.
- Subjects
DEMETHYLATION; SPINAL injections; DNA-binding proteins; PROMOTERS (Genetics); DRUG side effects; GENE ontology
- Publication
International Journal of Cancer, 2020, Vol 147, Issue 9, p2503
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.33106