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骨癌痛中由 EREG/EGFR-ERK-Runx1 信号激活的 HDAC2 介导的 kcnq2/kcnq3 基因转录抑制参与。

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

机构信息

Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center and Neuroscience Research Institute, Peking University, Beijing, China.

Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Beijing, 100191, China.

出版信息

Cell Commun Signal. 2024 Aug 27;22(1):416. doi: 10.1186/s12964-024-01797-2.

DOI:10.1186/s12964-024-01797-2
PMID:39192337
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11350972/
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.

摘要

骨癌疼痛（BCP）是癌症伴骨转移患者中常见的症状，但其潜在机制仍不清楚。本研究探讨了 Kv7（KCNQ）/M 钾通道在 DRG 神经元中转录调控机制及其在大鼠 BCP 发展中的作用。我们发现，HDAC2 介导的 kcnq2/kcnq3 基因转录抑制，该基因编码背根神经节（DRG）中的 Kv7（KCNQ）/M 钾通道，导致 DRG 神经元敏化和大鼠 BCP 的发病机制。此外，HDAC2 需要与 MeCP2 和 Sin3A 形成核心抑制复合物来执行 kcnq2/kcnq3 基因的转录调控。此外，我们鉴定出 EREG 是 HDAC2 介导的 kcnq2/kcnq3 基因转录抑制的上游信号分子。EGER/EGFR-ERK-Runx1 信号的激活，随后在 DRG 神经元中诱导 HDAC2 介导的 kcnq2/kcnq3 基因转录抑制，导致荷瘤大鼠神经元过度兴奋和痛觉过敏。因此，EGER/EGFR-ERK-Runx1 信号的激活，以及随后在 DRG 神经元中由 HDAC2 介导的 kcnq2/kcnq3 基因的转录抑制，是导致 DRG 神经元敏化和大鼠 BCP 发病机制的基础。这些发现揭示了一种潜在的可靶向机制，可能导致癌症患者骨转移相关疼痛。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/a61fce2572b0/12964_2024_1797_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/8b9e35b42160/12964_2024_1797_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/6dd1cefbcdbe/12964_2024_1797_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/a61fce2572b0/12964_2024_1797_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/8b9e35b42160/12964_2024_1797_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/eb915abd258f/12964_2024_1797_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/cd6beab72ec3/12964_2024_1797_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/5d9be2ac6d56/12964_2024_1797_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/2011c95f2070/12964_2024_1797_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/e8572e1ba8fd/12964_2024_1797_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/6dd1cefbcdbe/12964_2024_1797_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/080c/11350972/a61fce2572b0/12964_2024_1797_Fig8_HTML.jpg

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