骨癌痛（BCP）是骨转移癌症患者的一种普遍症状，但其潜在机制仍然难以捉摸。本研究探讨了DRG神经元Kv7(KCNQ)/M钾通道的转录调控机制及其在大鼠BCP发生中的作用。我们发现 HDAC2 介导的 kcnq2/kcnq3 基因（编码背根神经节 (DRG) 中的 Kv7(KCNQ)/M 钾通道）的转录抑制有助于 DRG 神经元的敏化和大鼠 BCP 的发病机制。此外，HDAC2 需要与 MeCP2 和 Sin3A 形成辅阻遏物复合物，以执行 kcnq2/kcnq3 基因的转录调控。此外，EREG 被确定为 HDAC2 介导的 kcnq2/kcnq3 基因转录抑制的上游信号分子。 EREG/EGFR-ERK-Runx1 信号传导的激活，随后诱导 HDAC2 介导的 DRG 神经元中 kcnq2/kcnq3 基因的转录抑制，导致荷瘤大鼠的神经元过度兴奋和疼痛超敏反应。因此，EREG/EGFR-ERK-Runx1 信号传导的激活，以及随后 DRG 神经元中 HDAC2 对 kcnq2/kcnq3 基因的转录抑制，是大鼠 DRG 神经元致敏和 BCP 发病机制的基础。这些发现揭示了导致癌症患者骨转移相关疼痛的潜在可靶向机制。© 2024。作者。

Bone cancer pain (BCP) represents a prevalent symptom among cancer patients with bone metastases, yet its underlying mechanisms remain elusive. This study investigated the transcriptional regulation mechanism of Kv7(KCNQ)/M potassium channels in DRG neurons and its involvement in the development of BCP in rats. We show that HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes, which encode Kv7(KCNQ)/M potassium channels in dorsal root ganglion (DRG), contributes to the sensitization of DRG neurons and the pathogenesis of BCP in rats. Also, HDAC2 requires the formation of a corepressor complex with MeCP2 and Sin3A to execute transcriptional regulation of kcnq2/kcnq3 genes. Moreover, EREG is identified as an upstream signal molecule for HDAC2-mediated kcnq2/kcnq3 genes transcription repression. Activation of EREG/EGFR-ERK-Runx1 signaling, followed by the induction of HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes in DRG neurons, leads to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. Consequently, the activation of EREG/EGFR-ERK-Runx1 signaling, along with the subsequent transcriptional repression of kcnq2/kcnq3 genes by HDAC2 in DRG neurons, underlies the sensitization of DRG neurons and the pathogenesis of BCP in rats. These findings uncover a potentially targetable mechanism contributing to bone metastasis-associated pain in cancer patients.© 2024. The Author(s).