GATA3-dependent epigenetic upregulation of CCL21 is involved in the development of neuropathic pain induced by bortezomib

• Published in: Molecular pain Vol. 15; p. 1744806919863292
• Main Authors: Zheng, Yaochao, Sun, Yang, Yang, Yanling, Zhang, Subo, Xu, Ting, Xin, Wenjun, Wu, Shaoling, Zhang, Xiangzhong
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.01.2019; Sage Publications Ltd
• Subjects: Acetylation; Bortezomib; CCL21 protein; Chemokines; Chromatin; CREB-binding protein; Cyclic AMP response element-binding protein; DNA microarrays; Dorsal horn; Epigenetics; GATA-3 protein; GATA-binding protein; Gene expression; Histone H3; Histones; Immunoprecipitation; Neuralgia; Pain; Pain perception; Quality of life; siRNA; Transcription; Up-regulation; neuropathic pain; Bortezomib; GATA3; CCL21
• ISSN: 1744-8069; 1744-8069
• DOI: 10.1177/1744806919863292

The incidence of bortezomib-induced neuropathic pain hampers the progress of therapy for neoplasia and also negatively affects the quality of life of patients. However, the molecular mechanism underlying bortezomib-induced neuropathic pain remains unknown. In this study, we found that the application of bortezomib significantly increased the expression of GATA-binding protein 3 (GATA3) in the spinal dorsal horn, and intrathecal administration of GATA3 siRNA attenuated mechanical allodynia. Furthermore, chromatin immunoprecipitation sequencing showed that bortezomib treatment induced the redistribution of GATA3 to transcriptional relevant regions. Notably, combined with the results of mRNA microarray, we found that C–C motif chemokine ligand 21 (CCL21) had an increased GATA3 binding and upregulated mRNA expression in the dorsal horn after bortezomib treatment. Next, we found that bortezomib treatment induced CCL21 upregulation in the spinal neurons, which was significantly reduced upon GATA3 silencing. Blockade of CCL21 using the neutralizing antibody or special siRNA ameliorated mechanical allodynia induced by bortezomib. In addition, bortezomib treatment increased the acetylation of histone H3 and the interaction between GATA3 and CREB-binding protein. GATA3 siRNA suppressed the CCL21 upregulation by decreasing the acetylation of histone H3. Together, these results suggested that activation of GATA3 mediated the epigenetic upregulation of CCL21 in dorsal horn neurons, which contributed to the bortezomib-induced neuropathic pain.