DNMT3a-triggered Downregulation of K 1.1 Gene in Primary Sensory Neurons Contributes to Paclitaxel-induced Neuropathic Pain

Overview

Journal Int J Cancer

Specialty Oncology

Date 2019 Jan 27

PMID 30684388

Citations 30

Authors

Qingxiang Mao

Shaogen Wu

Xiyao Gu

Shibin Du

Kai Mo

Linlin Sun

Jing Cao

Alex Bekker

Liyong Chen

Yuan-Xiang Tao

Affiliations

Soon will be listed here.

Abstract

Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 1.1 mRNA and its coding K 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K 1.1 and mimicking this increase reduces DRG K 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K 1.1 may contribute to chemotherapy-induced neuropathic pain.

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