DNMT3b SUMOylation Mediated MMP-2 Upregulation Contribute to Paclitaxel Induced Neuropathic Pain

Abstract

Paclitaxel is a common chemotherapeutic agent in cancer treatment, while it often causes chemotherapy-induced peripheral neuropathy (CIPN), which manifested as hyperalgesia and allodynia, and its mechanism remains largely unknown. The previous study has shown that matrix metalloproteinase-2 (MMP-2) plays a pivotal role in spinal nerve ligation (SNL) induced neuropathic pain, but its function in CIPN and exact molecular mechanisms underlying upregulation is not explored. Our present study revealed that MMP-2 is also upregulated in paclitaxel induced neuropathic pain (NP), and knockdown it by siRNA can ameliorate mechanical allodynia. Since DNA methylation is closely related to gene transcription, we explored the methylation status of the MMP-2 gene and demonstrated that MMP-2 upregulation is related to the reduced methylation level of its promoter. DNA methylation is mediated by DNA methyltransferases (DNMTs), and previous studies suggested that three main types of DNMTs can undergo SUMOylation. Our next study revealed that SUMO1 modification of DNMT3b is significantly enhanced. Intrathecal administration of SUMOylation inhibitor, ginkgolic acid (GA), could reverse enhanced SUMO1 modification of DNMT3b and upregulation of MMP-2 in the model rats. Further investigation suggested that DNMT3b binding activity to the promoter region of the MMP-2 gene is significantly decreased in paclitaxel treated rats, and the administration of GA can reverse these effects, which is also accompanied by changes in the promoter methylation status of the MMP-2 gene. Our study demonstrates that MMP-2 up-regulation mediated by DNMT3b SUMOylation is essential for paclitaxel induced NP development, which brings us new therapeutic options for CIPN.