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。

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
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
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引用次数: 0

摘要

全基因组关联研究(GWASs)已经确定了许多与前列腺癌相关的风险位点,但揭示其功能意义仍然难以捉摸。利用我们的高通量SNP -seq方法,我们在多祖先gwas发现的2525位点中确定了rs4519489作为潜在的功能SNP,因为它在蛋白质结合方面存在显着的等位基因差异。本文采用多种队列数据和实验模型,对rs4519489及其相关基因NOL10进行了综合分析。临床结果显示rs4519489基因型与NOL10表达对前列腺癌预后及严重程度有协同作用。通过无偏倚的蛋白质组学筛选,我们发现rs4519489的风险等位基因A与USF1的结合增强,USF1是一种致癌转录因子(TF),与前列腺癌的进展和预后有关,导致NOL10表达升高。此外,我们阐明了NOL10调节细胞周期通路,促进前列腺癌的进展。NOL10和USF1同时表达与侵袭性前列腺癌的特征和较差的预后相关。总之,我们的研究通过高通量SNP -seq和无偏倚蛋白质组学为功能性SNP筛选和TF鉴定提供了强有力的策略,突出了rs4519489-USF1-NOL10调控轴作为前列腺癌临床诊断和治疗的有前景的生物标志物或治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
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.
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