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The FOSB-IGFBP5-IGF-1 axis: a novel regulatory pathway that suppresses prostate cancer growth

Cancer Gene Therapy (2026)Cite this article

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Abstract

While the functions of activator protein-1 (AP-1) family transcription factors in prostate cancer (PCa) have been well researched, the specific role and mechanisms of FOSB in PCa progression are poorly understood. Here, we aimed to elucidate the precise role of FOSB in PCa and its underlying molecular mechanisms. A comprehensive investigation involving bioinformatics analysis of the TCGA and GEO datasets, validation in clinical PCa samples and cell lines, functional studies in vitro and in vivo, and RNA sequencing coupled with targeted validation (dual-luciferase reporter assays, ChIP‒qPCR, RT‒qPCR, Western blotting, and immunohistochemistry) was performed. FOSB is downregulated in PCa, and its high expression in tumours may reduce the risk of PCa progression by influencing characteristic growth-related cancer pathways. FOSB overexpression significantly inhibited PCa cell proliferation, increased apoptosis in vitro, and attenuated tumour growth in vivo, whereas FOSB knockdown resulted in the opposite effects. Mechanistically, FOSB transcripts were enriched in cell nuclei, where they upregulated the expression of IGFBP5, a gene that modulates the cellular response to IGF-1. This FOSB-mediated upregulation of IGFBP5 expression subsequently weakened the susceptibility of IGF1R to IGF-1 stimulation and suppressed the downstream PI3K/Akt and Ras/Raf/ERK oncogenic pathways. Our findings identify the novel FOSB–IGFBP5–IGF-1 axis upstream of PI3K/Akt and Ras/Raf/ERK signalling as a key regulator of PCa progression.

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Fig. 1: FOSB expression patterns and clinical associations in prostate cancer.
Fig. 2: Effects of FOSB overexpression and knockdown on PCa cell growth in vivo and in vitro.
Fig. 3: The regulatory relationship between FOSB expression and androgen receptor signalling activity.
Fig. 4: FOSB upregulated IGFBP5 expression in PCa.
Fig. 5: FOSB inhibited prostate cancer growth by suppressing IGF1R activity, which was dependent on the binding of IGFBP5 to IGF-1.
Fig. 6: Single-cell transcriptomics reanalysis identified FOSB as a key marker and revealed its association with the IGFBP5, and insulin signalling pathway activity in PCa.
Fig. 7: FOSB regulates prostate cancer growth by suppressing the PI3K/Akt and Ras/Raf/ERK pathways through the inactivation of IGF1R.

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Data availability

The RNA sequencing data discussed in this publication have been deposited in Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series accession number GSE304134. The single-cell dataset generated in this study is available from GEO under the accession numbers GSE221603 and GSE206962. The public data analysed in this study are available from GEO under the accessions GSE200879 and GSE46602. The TCGA prostate adenocarcinoma (PRAD) dataset was downloaded from UCSC Xena (https://xenabrowser.net/datapages/). All the scripts used for data processing and analysis are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to acknowledge Guangzhou Science and Technology Plan Project, Guangzhou Health Technology Project, Panyu District Science and Technology Plan Project for their support.

Funding

This work was supported by the National Key Research and Development Program of China (No. 2023YFE0204500), and the National Natural Science Foundation of China (No. 82272856).

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  1. These authors contributed equally: Jun Huang, Sheng-Dong Ge, Ling-Lan Zhao, Xian-Lu Song.

Authors and Affiliations

  1. Department of Urology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, PR China

    Jun Huang, Sheng-Dong Ge, Ling-Lan Zhao, Qu Li, Xiao-Feng Liu, Qing Li, Tao Wang & Shan-Chao Zhao

  2. Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China

    Ling-Lan Zhao & Wen-Jun Tang

  3. Department of Radiotherapy, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, PR China

    Xian-Lu Song

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Contributions

SCZ, QingL, and TW conceived and designed the experiments. JH performed the experiments. JH, SDG, LLZ, and XLS acquired and analysed the data. JH wrote this manuscript. QuL, XFL, and WJT checked the manuscript. All the authors have read and approved the final manuscript.

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Correspondence to Tao Wang or Shan-Chao Zhao.

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This study adhered to the guidelines for animal and human research ethics. The animal experiments in this study were reviewed and approved by the Animal Ethical and Welfare Committee (AEWC) (Approval No. IAEC-K-230615-04). Human study protocols were approved by the Jiangmen Central Hospital Ethics Committee (Approval No. [2023]51), Jiangmen, China. Written informed consent, detailing the study’s objectives, was obtained from all participants.

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Huang, J., Ge, SD., Zhao, LL. et al. The FOSB-IGFBP5-IGF-1 axis: a novel regulatory pathway that suppresses prostate cancer growth. Cancer Gene Ther (2026). https://doi.org/10.1038/s41417-026-01012-z

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