{"title":"结合snp测序和等位基因特异性蛋白质组学捕获揭示了2525前列腺癌易感位点的功能因果关系。","authors":"Dandan Dong, Zixian Wang, Mengqi Liu, Qin Zhang, Wenjie Xu, Yu Wei, Jing Zhu, Xiayun Yang, Qixiang Zhang, Yao Zhu, Liang Wang, Peng Zhang, Gong-Hong Wei","doi":"10.1038/s41467-025-64005-w","DOIUrl":null,"url":null,"abstract":"<p><p>Genome wide association studies (GWASs) have identified numerous risk loci associated with prostate cancer, yet unraveling their functional significance remains elusive. Leveraging our high-throughput SNPs-seq method, we pinpointed rs4519489 within the multi-ancestry GWAS-discovered 2p25 locus as a potential functional SNP due to its significant allelic differences in protein binding. Here, we conduct a comprehensive analysis of rs4519489 and its associated gene, NOL10, employing diverse cohort data and experimental models. Clinical findings reveal a synergistic effect between rs4519489 genotype and NOL10 expression on prostate cancer prognosis and severity. Through unbiased proteomics screening, we reveal that the risk allele A of rs4519489 exhibits enhanced binding to USF1, an oncogenic transcription factor (TF) implicated in prostate cancer progression and prognosis, resulting in elevated NOL10 expression. Furthermore, we elucidate that NOL10 regulates cell cycle pathways, fostering prostate cancer progression. The concurrent expression of NOL10 and USF1 correlates with aggressive prostate cancer characteristics and poorer prognosis. Collectively, our study offers a robust strategy for functional SNP screening and TF identification through high-throughput SNPs-seq and unbiased proteomics, highlighting the rs4519489-USF1-NOL10 regulatory axis as a promising biomarker or therapeutic target for clinical diagnosis and treatment of prostate cancer.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"16 1","pages":"8950"},"PeriodicalIF":15.7000,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508145/pdf/","citationCount":"0","resultStr":"{\"title\":\"Combined SNPs sequencing and allele specific proteomics capture reveal functional causality underpinning the 2p25 prostate cancer susceptibility locus.\",\"authors\":\"Dandan Dong, Zixian Wang, Mengqi Liu, Qin Zhang, Wenjie Xu, Yu Wei, Jing Zhu, Xiayun Yang, Qixiang Zhang, Yao Zhu, Liang Wang, Peng Zhang, Gong-Hong Wei\",\"doi\":\"10.1038/s41467-025-64005-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Genome wide association studies (GWASs) have identified numerous risk loci associated with prostate cancer, yet unraveling their functional significance remains elusive. Leveraging our high-throughput SNPs-seq method, we pinpointed rs4519489 within the multi-ancestry GWAS-discovered 2p25 locus as a potential functional SNP due to its significant allelic differences in protein binding. Here, we conduct a comprehensive analysis of rs4519489 and its associated gene, NOL10, employing diverse cohort data and experimental models. Clinical findings reveal a synergistic effect between rs4519489 genotype and NOL10 expression on prostate cancer prognosis and severity. Through unbiased proteomics screening, we reveal that the risk allele A of rs4519489 exhibits enhanced binding to USF1, an oncogenic transcription factor (TF) implicated in prostate cancer progression and prognosis, resulting in elevated NOL10 expression. Furthermore, we elucidate that NOL10 regulates cell cycle pathways, fostering prostate cancer progression. The concurrent expression of NOL10 and USF1 correlates with aggressive prostate cancer characteristics and poorer prognosis. Collectively, our study offers a robust strategy for functional SNP screening and TF identification through high-throughput SNPs-seq and unbiased proteomics, highlighting the rs4519489-USF1-NOL10 regulatory axis as a promising biomarker or therapeutic target for clinical diagnosis and treatment of prostate cancer.</p>\",\"PeriodicalId\":19066,\"journal\":{\"name\":\"Nature Communications\",\"volume\":\"16 1\",\"pages\":\"8950\"},\"PeriodicalIF\":15.7000,\"publicationDate\":\"2025-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508145/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Communications\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1038/s41467-025-64005-w\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-64005-w","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Combined SNPs sequencing and allele specific proteomics capture reveal functional causality underpinning the 2p25 prostate cancer susceptibility locus.
Genome wide association studies (GWASs) have identified numerous risk loci associated with prostate cancer, yet unraveling their functional significance remains elusive. Leveraging our high-throughput SNPs-seq method, we pinpointed rs4519489 within the multi-ancestry GWAS-discovered 2p25 locus as a potential functional SNP due to its significant allelic differences in protein binding. Here, we conduct a comprehensive analysis of rs4519489 and its associated gene, NOL10, employing diverse cohort data and experimental models. Clinical findings reveal a synergistic effect between rs4519489 genotype and NOL10 expression on prostate cancer prognosis and severity. Through unbiased proteomics screening, we reveal that the risk allele A of rs4519489 exhibits enhanced binding to USF1, an oncogenic transcription factor (TF) implicated in prostate cancer progression and prognosis, resulting in elevated NOL10 expression. Furthermore, we elucidate that NOL10 regulates cell cycle pathways, fostering prostate cancer progression. The concurrent expression of NOL10 and USF1 correlates with aggressive prostate cancer characteristics and poorer prognosis. Collectively, our study offers a robust strategy for functional SNP screening and TF identification through high-throughput SNPs-seq and unbiased proteomics, highlighting the rs4519489-USF1-NOL10 regulatory axis as a promising biomarker or therapeutic target for clinical diagnosis and treatment of prostate cancer.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.