NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel
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, microarray analysis were performed to explore the molecular mechanism.
Results: We found that paclitaxel treatment increased the 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 TSS of target genes in dorsal horn after paclitaxel treatment.
We further found that NFATc2 occupancy directly upregulated 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.
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Posted 18 Jun, 2020
On 18 Oct, 2020
On 05 Jul, 2020
Received 04 Jul, 2020
On 20 Jun, 2020
Received 20 Jun, 2020
Invitations sent on 19 Jun, 2020
On 19 Jun, 2020
On 17 Jun, 2020
On 16 Jun, 2020
On 15 Jun, 2020
On 15 Jun, 2020
NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel
Posted 18 Jun, 2020
On 18 Oct, 2020
On 05 Jul, 2020
Received 04 Jul, 2020
On 20 Jun, 2020
Received 20 Jun, 2020
Invitations sent on 19 Jun, 2020
On 19 Jun, 2020
On 17 Jun, 2020
On 16 Jun, 2020
On 15 Jun, 2020
On 15 Jun, 2020
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, microarray analysis were performed to explore the molecular mechanism.
Results: We found that paclitaxel treatment increased the 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 TSS of target genes in dorsal horn after paclitaxel treatment.
We further found that NFATc2 occupancy directly upregulated 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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6