基于G4筛选和机器学习的用于前列腺癌症的G4-调节免疫相关药物靶点的鉴定
Identification of G4-regulated immune-related drug targets for prostate cancer based on G4 screen and machine learning.
摘要(中文译文)
G-四链体（G-quadruplex，G4）结构是重要的表观遗传调控因子，也是癌症的潜在治疗靶点。然而，其在前列腺癌中的作用，尤其是与免疫微环境的关系，仍知之甚少。我们采用BG4 ChIP-seq技术绘制了前列腺癌细胞系C4-2的全基因组G4结构图谱。生物信息学分析将G4相关基因与免疫通路富集分析及机器学习算法（LASSO、SVM-RFE、GBM、朴素贝叶斯和GLM）相结合，以鉴定前列腺癌进展中的核心基因。利用GTEx、TCGA和HPA的临床数据分析了基因表达与生存预后。功能验证包括qPCR、CCK-8、集落形成和划痕愈合实验。采用DrugnomeAI评估可成药性，并利用RFdiffusion和ProteinMPNN进行人工智能辅助的肽设计。我们鉴定了1,289个前列腺癌特异性G4结构，主要位于启动子区域。机器学习和免疫富集分析确定IKBKB为前列腺癌进展中的关键核心基因。IKBKB在前列腺癌组织中过表达，与晚期分期和不良预后相关，并受启动子G4结构通过转录因子AR和ERG调控。IKBKB促进基因组不稳定性、肿瘤干性和免疫微环境重塑。G4稳定化增加了IKBKB表达并激活NF-κB通路，增强癌细胞的活力、增殖和迁移能力。计算筛选证实了IKBKB的可成药性，并鉴定了潜在抑制剂（如金诺芬）。人工智能辅助设计生成了靶向IKBKB的肽抑制剂以及用于G4破坏的CRISPR-dCas9策略。IKBKB是受G4调控的、与免疫相关的前列腺癌进展驱动因子。其过表达与NF-κB激活、基因组不稳定性及免疫微环境改变相关。本研究提出了两种新型治疗策略：破坏IKBKB启动子处的G4结构以及人工智能设计的肽抑制剂。这些发现为前列腺癌中表观遗传靶向与免疫治疗的联合应用提供了框架。
Abstract
G-quadruplex (G4) structures are important epigenetic regulators and potential therapeutic targets in cancer. However, their role in prostate cancer, particularly in relation to the immune microenvironment, remains poorly understood. We performed BG4 ChIP-seq to map genome-wide G4 structures in the prostate cancer cell line C4-2. Bioinformatics analyses integrated G4-associated genes with immune pathway enrichment and machine learning algorithms (LASSO, SVM-RFE, GBM, Naïve Bayes, and GLM) to identify hub genes in prostate cancer progression. Clinical data from GTEx, TCGA, and HPA were analyzed for expression and survival. Functional validation included qPCR, CCK-8, colony formation, and wound-healing assays. Druggability was assessed using DrugnomeAI, and AI-assisted peptide design was performed with RFdiffusion and ProteinMPNN. We identified 1,289 prostate cancer-specific G4 structures, predominantly in promoter regions. Machine learning and immune enrichment analysis pinpointed IKBKB as a key hub gene in prostate cancer progression. IKBKB was overexpressed in prostate cancer tissues, correlated with advanced stage and poor prognosis, and was regulated by promoter G4 structures via transcription factors AR and ERG. IKBKB promoted genome instability, tumor stemness, and immune microenvironment remodeling. G4 stabilization increased IKBKB expression and activated the NF-κB pathway, enhancing cancer cell viability, proliferation, and migration. Computational screening confirmed IKBKB's druggability and identified potential inhibitors (e.g., Auranofin). AI-assisted design generated peptide inhibitors targeting IKBKB and a CRISPR-dCas9 strategy for G4 disruption. IKBKB is a G4-regulated, immune-related driver of prostate cancer progression. Its overexpression is linked to NF-κB activation, genomic instability, and immune microenvironment alterations. The study proposes two novel therapeutic strategies: G4 disruption at the IKBKB promoter and AI-designed peptide inhibitors. These findings provide a framework for combining epigenetic targeting with immunotherapy in prostate cancer.
如何引用
AMA
Liu Ge, Yue Hou, Xuan Huang, Jiawei Zhang, Lin Yao, Saisai Chen, et al. Identification of G4-regulated immune-related drug targets for prostate cancer based on G4 screen and machine learning.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1806289.
APA
Liu Ge, Yue Hou, Xuan Huang, Jiawei Zhang, Lin Yao, Saisai Chen, et al (2026). Identification of G4-regulated immune-related drug targets for prostate cancer based on G4 screen and machine learning.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1806289
GB/T 7714
Liu Ge, Yue Hou, Xuan Huang, Jiawei Zhang, Lin Yao, Saisai Chen, et al. Identification of G4-regulated immune-related drug targets for prostate cancer based on G4 screen and machine learning.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1806289.
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