NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel
Abstract Background The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods Paw withdrawal threshold was measur...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-10-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01992-1 |
| _version_ | 1818229293139886080 |
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| author | Meng Liu Su-Bo Zhang Yu-Xuan Luo Yan-Ling Yang Xiang-Zhong Zhang Bo Li Yan Meng Yuan-Jie Chen Rui-Xian Guo Yuan-Chang Xiong Wen-Jun Xin Dai Li |
| author_facet | Meng Liu Su-Bo Zhang Yu-Xuan Luo Yan-Ling Yang Xiang-Zhong Zhang Bo Li Yan Meng Yuan-Jie Chen Rui-Xian Guo Yuan-Chang Xiong Wen-Jun Xin Dai Li |
| author_sort | Meng Liu |
| collection | DOAJ |
| description | Abstract Background The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism. Results We found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain. |
| first_indexed | 2024-12-12T10:16:18Z |
| format | Article |
| id | doaj.art-f2b86f125c4347bb9a3587344951ac27 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-12T10:16:18Z |
| publishDate | 2020-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-f2b86f125c4347bb9a3587344951ac272022-12-22T00:27:39ZengBMCJournal of Neuroinflammation1742-20942020-10-0117111210.1186/s12974-020-01992-1NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxelMeng Liu0Su-Bo Zhang1Yu-Xuan Luo2Yan-Ling Yang3Xiang-Zhong Zhang4Bo Li5Yan Meng6Yuan-Jie Chen7Rui-Xian Guo8Yuan-Chang Xiong9Wen-Jun Xin10Dai Li11Neuroscience Program, The Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen UniversityNeuroscience Program, The Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Anesthesiology, Changhai Hospital, Naval Medical UniversityDepartment of Anesthesiology, Changhai Hospital, Naval Medical UniversityDepartment of Anesthesiology, Changhai Hospital, Naval Medical UniversityNeuroscience Program, The Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen UniversityDepartment of Anesthesiology, Changhai Hospital, Naval Medical UniversityNeuroscience Program, The Fifth Affiliated Hospital of Sun Yat-Sen University, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen UniversityDepartment of Anesthesiology, Changhai Hospital, Naval Medical UniversityAbstract Background The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism. Results We found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.http://link.springer.com/article/10.1186/s12974-020-01992-1PaclitaxelNFATc2CXCL14Histone acetylationNeuropathic pain |
| spellingShingle | Meng Liu Su-Bo Zhang Yu-Xuan Luo Yan-Ling Yang Xiang-Zhong Zhang Bo Li Yan Meng Yuan-Jie Chen Rui-Xian Guo Yuan-Chang Xiong Wen-Jun Xin Dai Li NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel Journal of Neuroinflammation Paclitaxel NFATc2 CXCL14 Histone acetylation Neuropathic pain |
| title | NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel |
| title_full | NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel |
| title_fullStr | NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel |
| title_full_unstemmed | NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel |
| title_short | NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel |
| title_sort | nfatc2 dependent epigenetic upregulation of cxcl14 is involved in the development of neuropathic pain induced by paclitaxel |
| topic | Paclitaxel NFATc2 CXCL14 Histone acetylation Neuropathic pain |
| url | http://link.springer.com/article/10.1186/s12974-020-01992-1 |
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