A positive feedback loop between HNRNPF and GRHL2 drives NEK8-mediated prostate cancer progression

Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, especially in advanced stages. The role of Heterogeneous Nuclear Ribonucleoprotein F (HNRNPF) in PCa progression is poorly defined. The function and mechanism of HNRNPF were investigated using in vitro assays, xenograft and bone metastasis models, and integrative molecular analyses including RNA sequencing, RNA immunoprecipitation, chromatin immunoprecipitation, actinomycin D chase, and dual-luciferase reporter assays. HNRNPF was significantly upregulated in PCa tissues and cell lines, and its expression positively correlated with advanced T stage, Gleason score, PSA levels, and poor prognosis. Functional assays showed that HNRNPF promotes proliferation, migration, invasion, and tumor growth. Mechanistically, HNRNPF binds AU-rich elements within the 3′ UTR of GRHL2 mRNA, enhancing its stability. GRHL2 transcriptionally activates NEK8, which sustains c-Myc expression and mediates the oncogenic effects of HNRNPF. In turn, GRHL2 directly upregulates HNRNPF transcription, forming a positive feedback loop that drives tumor progression. The HNRNPF–GRHL2–NEK8–c-Myc axis represents a novel regulatory network promoting PCa progression and highlights HNRNPF as a potential biomarker and therapeutic target.