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NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin

Neuropathic pain is a common dose-limiting side effect of oxaliplatin, which hampers the effective treatment of tumors. Here, we found that upregulation of transcription factor NFATc2 decreased the expression of Beclin-1, a critical molecule in autophagy, in the spinal dorsal horn, and contributed t...

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Autores principales: Liu, Meng, Mai, Jing-Wen, Luo, De-Xing, Liu, Guan-Xi, Xu, Ting, Xin, Wen-Jun, Lin, Su-Yan, Li, Zhen-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9941598/
https://www.ncbi.nlm.nih.gov/pubmed/36733258
http://dx.doi.org/10.1177/17448069231158289
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author Liu, Meng
Mai, Jing-Wen
Luo, De-Xing
Liu, Guan-Xi
Xu, Ting
Xin, Wen-Jun
Lin, Su-Yan
Li, Zhen-Yu
author_facet Liu, Meng
Mai, Jing-Wen
Luo, De-Xing
Liu, Guan-Xi
Xu, Ting
Xin, Wen-Jun
Lin, Su-Yan
Li, Zhen-Yu
author_sort Liu, Meng
collection PubMed
description Neuropathic pain is a common dose-limiting side effect of oxaliplatin, which hampers the effective treatment of tumors. Here, we found that upregulation of transcription factor NFATc2 decreased the expression of Beclin-1, a critical molecule in autophagy, in the spinal dorsal horn, and contributed to neuropathic pain following oxaliplatin treatment. Meanwhile, manipulating autophagy levels by intrathecal injection of rapamycin (RAPA) or 3-methyladenine (3-MA) differentially altered mechanical allodynia in oxaliplatin-treated or naïve rats. Utilizing chromatin immunoprecipitation-sequencing (ChIP-seq) assay combined with bioinformatics analysis, we found that NFATc2 negatively regulated the transcription of tuberous sclerosis complex protein 2 (TSC2), which contributed to the oxaliplatin-induced Beclin-1 downregulation. Further assays revealed that NFATc2 regulated histone H4 acetylation and methylation in the TSC2 promoter site 1 in rats’ dorsal horns with oxaliplatin treatment. These results suggested that NFATc2 mediated the epigenetic downregulation of the TSC2/Beclin-1 autophagy pathway and contributed to oxaliplatin-induced mechanical allodynia, which provided a new therapeutic insight for chemotherapy-induced neuropathic pain.
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spelling pubmed-99415982023-02-22 NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin Liu, Meng Mai, Jing-Wen Luo, De-Xing Liu, Guan-Xi Xu, Ting Xin, Wen-Jun Lin, Su-Yan Li, Zhen-Yu Mol Pain Research Article Neuropathic pain is a common dose-limiting side effect of oxaliplatin, which hampers the effective treatment of tumors. Here, we found that upregulation of transcription factor NFATc2 decreased the expression of Beclin-1, a critical molecule in autophagy, in the spinal dorsal horn, and contributed to neuropathic pain following oxaliplatin treatment. Meanwhile, manipulating autophagy levels by intrathecal injection of rapamycin (RAPA) or 3-methyladenine (3-MA) differentially altered mechanical allodynia in oxaliplatin-treated or naïve rats. Utilizing chromatin immunoprecipitation-sequencing (ChIP-seq) assay combined with bioinformatics analysis, we found that NFATc2 negatively regulated the transcription of tuberous sclerosis complex protein 2 (TSC2), which contributed to the oxaliplatin-induced Beclin-1 downregulation. Further assays revealed that NFATc2 regulated histone H4 acetylation and methylation in the TSC2 promoter site 1 in rats’ dorsal horns with oxaliplatin treatment. These results suggested that NFATc2 mediated the epigenetic downregulation of the TSC2/Beclin-1 autophagy pathway and contributed to oxaliplatin-induced mechanical allodynia, which provided a new therapeutic insight for chemotherapy-induced neuropathic pain. SAGE Publications 2023-02-20 /pmc/articles/PMC9941598/ /pubmed/36733258 http://dx.doi.org/10.1177/17448069231158289 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Research Article
Liu, Meng
Mai, Jing-Wen
Luo, De-Xing
Liu, Guan-Xi
Xu, Ting
Xin, Wen-Jun
Lin, Su-Yan
Li, Zhen-Yu
NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin
title NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin
title_full NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin
title_fullStr NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin
title_full_unstemmed NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin
title_short NFATc2-dependent epigenetic downregulation of the TSC2/Beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin
title_sort nfatc2-dependent epigenetic downregulation of the tsc2/beclin-1 pathway is involved in neuropathic pain induced by oxaliplatin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9941598/
https://www.ncbi.nlm.nih.gov/pubmed/36733258
http://dx.doi.org/10.1177/17448069231158289
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