Detection of Genome-Wide IGF-1R Recruitment to Enhancer and Promoter Regions of Chromatin in Clinical Prostate Cancers

IF 3.1 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2025-09-30 DOI:10.1002/cam4.71257

Jack V. Mills, Avigail Taylor, Reema Singh, Jinseon Kim, Simon Engledow, Richard Colling, Clare Verrill, Ian G. Mills, Valentine M. Macaulay

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引用次数: 0

Abstract

Introduction

Nuclear insulin-like growth factor-1 receptor (IGF-1R) undergoes IGF-induced recruitment to cancer cell chromatin in vitro and associates with advanced prostate cancer (PCa) stage in clinical tissue, prompting this investigation of IGF-1R chromatin recruitment in vivo.

Methods

Human tissues surplus to diagnostic need were obtained from consenting patients undergoing transurethral resection of the prostate (TURP) or radical prostatectomy (RP). Initial tissue samples were processed for H3K4me1-positive control ChIP to optimise homogenisation, fixation and ChIP conditions. Following successful method optimization, IGF-1R and H3K4me1 ChIP-seq was performed on six treatment-naïve localized PCa samples, along with parallel IGF-1R immunohistochemistry analysis. MACS2 and LanceOtron peak callers were used to identify binding sites from ChIP-seq data and MEME Suite was used to identify an IGF-1R binding motif. In vitro chromatin immunoprecipitation qPCR (ChIP-qPCR) was used for ChIP-seq data validation.

Results

We identified 5743 unique IGF-1R binding sites, with 37% within 3 kb of gene transcription start sites (TSSs). Of these sites, 72.3% coincided with enhancer mark H3K4me1, suggesting regulatory function. Motif analysis identified an IGF-1R consensus binding motif for the first time, with a sequence resembling that of the insulin receptor and PITX2 transcription factor binding motifs, supporting functional similarities. In vitro ChIP-qPCR confirmed IGF-1R recruitment to a site identified in vivo in the RRM2 TSS, a gene involved in DNA replication and repair and regulated by the IGF-axis, highlighting potential regulatory function of nuclear IGF-1R.

Conclusion

Overall, these data represent the first characterization of genome-wide IGF-1R recruitment in PCa tissue and are consistent with a transcriptional regulatory role, further elucidating the contribution of nuclear IGF-1R to advanced clinical stage.

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临床前列腺癌中染色质增强子和启动子区域IGF-1R全基因组募集的检测

细胞核胰岛素样生长因子-1受体（IGF-1R）在体外经历igf诱导的癌细胞染色质募集，并与临床组织中的晚期前列腺癌（PCa）阶段相关，促使本研究在体内对IGF-1R染色质募集进行研究。方法：从经尿道前列腺切除术（TURP）或根治性前列腺切除术（RP）患者中获得诊断需要的人体组织。对初始组织样本进行h3k4me1阳性对照ChIP处理，以优化匀浆、固定和ChIP条件。方法优化成功后，对6个treatment-naïve定位PCa样本进行IGF-1R和H3K4me1 ChIP-seq，并进行IGF-1R免疫组化分析。使用MACS2和LanceOtron峰调用者从ChIP-seq数据中识别结合位点，使用MEME Suite识别IGF-1R结合基序。采用体外染色质免疫沉淀qPCR （ChIP-qPCR）对ChIP-seq数据进行验证。结果：我们鉴定出5743个独特的IGF-1R结合位点，其中37%位于基因转录起始位点（tss）的3kb内。在这些位点中，72.3%与增强子标记H3K4me1一致，提示具有调节功能。基序分析首次发现IGF-1R一致结合基序，其序列与胰岛素受体和PITX2转录因子结合基序相似，支持功能相似性。体外ChIP-qPCR证实了IGF-1R在RRM2 TSS（一个参与DNA复制和修复并受igf -轴调控的基因）中被募集到体内的一个位点，突出了核IGF-1R的潜在调节功能。结论：总的来说，这些数据首次表征了IGF-1R在PCa组织中的全基因组募集，并与转录调节作用一致，进一步阐明了核IGF-1R对晚期临床阶段的贡献。

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

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.