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

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.