title: Epigenetic upregulation of CXCL12 expression mediates antitubulin chemotherapeutics-induced neuropathic pain.
abstract: Clinically, Microtubule-targeted agents-induced neuropathic pain hampers chemotherapeutics for patients with cancer. Here, we found that application of paclitaxel or vincristine increased the protein and mRNA expression of CXCL12 and frequency and amplitude of miniature excitatory post synaptic currents (mEPSCs) in spinal dorsal horn neurons. Spinal local application of CXCL12 induced the long-term potentiation of nociceptive synaptic transmission and increased the amplitude of mEPSCs. Inhibition of CXCL12 using the transgenic mice (CXCL12) or neutralizing antibody or siRNA ameliorated the mEPSC's enhancement and mechanical allodynia. In addition, paclitaxel and vincristine both could increase the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the acetylation of histone H4 in the CXCL12-expressing neurons. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that antitubulin chemotherapeutics increased the binding of STAT3 to the CXCL12 gene promoter and the interaction between STAT3 and p300, and contributed to the enhanced transcription of CXCL12 by increasing the acetylation of histone H4 in CXCL12 gene promoter. Inhibition of STAT3 by intrathecal injection of adeno-associated virus encoding Cre and green fluorescent protein into STAT3 mice or inhibitor S3I-201 into rats suppressed the CXCL12 upsurge by decreasing the acetylation of histone H4. Finally, blockade of CXCR4 but not CXCR7 ameliorated the paclitaxel- or vincristine-induced mechanical allodynia. Together, these results suggested that enhanced interaction between STAT3 and p300 mediated the epigenetic upregulation of CXCL12 in dorsal horn neurons, which contributed to the antitubulin chemotherapeutics-induced persistent pain.
authors.affiliation: Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen Universtiy Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Han-Dong
authors.initials: HD
authors.lastname: Ou-Yang
authors.affiliation: Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Sun Yet-Sen University, Guangzhou, China.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Li
authors.affiliation: Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Cui-Cui
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Huang
authors.affiliation: Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jia-You
authors.initials: JY
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen Universtiy Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Bi-Lin
authors.initials: BL
authors.lastname: Nie
authors.affiliation: Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Rehabilitation Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Wu
authors.affiliation: Department of Forensic Medicine, Zhongshan Medical School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Xin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism*; D017239:Paclitaxel; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014404:Tubulin / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics; D014750:Vincristine
chemical_list: D000906:Antibodies; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014404:Tubulin; D014750:Vincristine; D017239:Paclitaxel