Histone modifications and Sp1 promote GPR160 expression in bone cancer pain within rodent models.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2024-10-24 DOI:10.1038/s44319-024-00292-6

Chengfei Xu, Yahui Wang, Chaobo Ni, Miao Xu, Chengyu Yin, Qiuli He, Bing Ma, Jie Fu, Baoxia Zhao, Liping Chen, Tong Zhi, Shirong Wei, Liang Cheng, Hui Xu, Jiajun Xiao, Lei Yang, Qingqing Xu, Jiao Kuang, Boyi Liu, Qinghe Zhou, Xuewu Lin, Ming Yao, Huadong Ni

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引用次数: 0

Abstract

Bone cancer pain (BCP) affects ~70% of patients in advanced stages, primarily due to bone metastasis, presenting a substantial therapeutic challenge. Here, we profile orphan G protein-coupled receptors in the dorsal root ganglia (DRG) following tumor infiltration, and observe a notable increase in GPR160 expression. Elevated Gpr160 mRNA and protein levels persist from postoperative day 6 for over 18 days in the affected DRG, predominantly in small-diameter C-fiber type neurons specific to the tibia. Targeted interventions, including DRG microinjection of siRNA or AAV delivery, mitigate mechanical allodynia, cold, and heat hyperalgesia induced by the tumor. Tumor infiltration increases DRG neuron excitability in wild-type mice, but not in Gpr160 gene knockout mice. Tumor infiltration results in reduced H3K27me3 and increased H3K27ac modifications, enhanced binding of the transcription activator Sp1 to the Gpr160 gene promoter region, and induction of GPR160 expression. Modulating histone-modifying enzymes effectively alleviated pain behavior. Our study delineates a novel mechanism wherein elevated Sp1 levels facilitate Gpr160 gene transcription in nociceptive DRG neurons during BCP in rodents.

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在啮齿动物模型中，组蛋白修饰和 Sp1 可促进骨癌疼痛中 GPR160 的表达。

骨癌疼痛（BCP）影响着约 70% 的晚期患者，主要是由于骨转移所致，给治疗带来了巨大挑战。在这里，我们对肿瘤浸润后背根神经节（DRG）中的孤儿G蛋白偶联受体进行了分析，观察到GPR160的表达明显增加。Gpr160 mRNA和蛋白水平的升高从术后第6天开始在受影响的DRG中持续超过18天，主要存在于胫骨特异的小直径C纤维型神经元中。靶向干预（包括 DRG 显微注射 siRNA 或 AAV 传播）可减轻肿瘤诱导的机械异感、冷痛和热痛。肿瘤浸润会增加野生型小鼠的DRG神经元兴奋性，但不会增加Gpr160基因敲除小鼠的DRG神经元兴奋性。肿瘤浸润导致 H3K27me3 减少和 H3K27ac 修饰增加，转录激活剂 Sp1 与 Gpr160 基因启动子区域的结合增强，并诱导 GPR160 的表达。调节组蛋白修饰酶可有效缓解疼痛行为。我们的研究阐明了一种新的机制，即在啮齿类动物的 BCP 过程中，Sp1 水平的升高促进了痛觉 DRG 神经元中 Gpr160 基因的转录。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.