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

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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Publication Details

Journal
EMBO Reports
Published
2024-10-24
DOI
https://doi.org/10.1038/s44319-024-00292-6
Citations
15
Primary Topic
Pain Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
4.90

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article

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

Shirong Wei, Hui Xu, Ming Yao, Qiuli He et al.
15 citations
EMBO Reports
Pain Mechanisms and Treatments
4.90
article

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

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

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.

EMBO ReportsVol. 25(12)
Bengbu Medical College (CN), Jiaxing University (CN), First Hospital of Jiaxing (CN), The Third Affiliated Hospital of Zhejiang Chinese Medical University (CN), The Second Affiliated Hospital of Bengbu Medical College (CN), First Affiliated Hospital of Bengbu Medical College (CN), Union Hospital (CN), Huazhong University of Science and Technology (CN)
National Natural Science Foundation of China, China Postdoctoral Science Foundation, National Clinical Key Specialty Project Foundation, Natural Science Foundation of Zhejiang Province
Good health and well-being
Openalex Percentile: Top 4%
Pain Mechanisms and Treatments
4.90
DOIOpen Access PDFOpenAlex
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