Involvement of HDAC2-mediated kcnq2/kcnq3 genes transcription repression activated by EREG/EGFR-ERK-Runx1 signaling in bone cancer pain.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2024-08-27 DOI:10.1186/s12964-024-01797-2

Zi-Xian Zhang, Yue Tian, Song Li, Hong-Bo Jing, Jie Cai, Min Li, Guo-Gang Xing

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Abstract

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.

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骨癌疼痛中EREG/EGFR-ERK-Runx1信号激活的HDAC2介导的kcnq2/kcnq3基因转录抑制的参与

骨癌痛（BCP）是骨转移癌症患者的一种普遍症状，但其潜在机制仍难以捉摸。本研究探讨了 DRG 神经元中 Kv7(KCNQ)/M 钾通道的转录调控机制及其与大鼠 BCP 发病的关系。我们发现，HDAC2介导的对背根神经节（DRG）中编码Kv7(KCNQ)/M钾通道的kcnq2/kcnq3基因的转录抑制有助于DRG神经元的敏化和大鼠BCP的发病。此外，HDAC2 需要与 MeCP2 和 Sin3A 形成一个核心抑制复合物，才能对 kcnq2/kcnq3 基因进行转录调控。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信号的激活，继而诱导DRG神经元中HDAC2介导的kcnq2/kcnq3基因转录抑制，导致肿瘤大鼠神经元过度兴奋和痛觉过敏。因此，EREG/EGFR-ERK-Runx1 信号的激活，以及随后 HDAC2 对 DRG 神经元中 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。这些发现揭示了癌症患者骨转移相关疼痛的潜在靶向机制。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.

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