Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer characterized by lineage plasticity and poor response to standard chemotherapy and androgen deprivation therapy. Although transcriptional mechanisms driving t-NEPC have been extensively studied, the contribution of post-transcriptional regulation remains less defined. Here, we report fibroblast growth factor 12 (FGF12) as a critical post-transcriptional regulator of t-NEPC progression. Transcriptomic analyses of patient biopsies, patient-derived xenografts, and prostate cancer cell models consistently demonstrated elevated FGF12 expression in t-NEPC, which was further validated by immunohistochemistry in archival specimens. Functional assays revealed that FGF12 expression conferred survival of cancer cells to chemotherapeutic agents, including etoposide and camptothecin. Integrative RNA sequencing and affinity purification–mass spectrometry showed that FGF12 mediates these functions mainly through interaction with the RNA-binding protein YB1, leading to stabilization of oncogenic long noncoding RNAs, including NEAT1 and MALAT1, whereas RNA silencing of YB1 abrogated the ability of FGF12 to upregulate these transcripts. Collectively, these findings uncover a previously unrecognized FGF12-YB1-lncRNA signaling axis that drives t-NEPC progression. Targeting this pathway may provide new therapeutic opportunities for patients with this aggressive disease.

Fibroblast growth factor 12 (FGF12), a member of the intracellular fibroblast growth factor homologous factor (FHF) subfamily, has been widely studied for its role in the modulation of voltage-gated ion channels. However, recent studies suggest that FGF12 possesses various cellular function beyond ion channel regulation, particularly in cancer progression. Accumulating evidence indicates that the upregulation of FGF12 is associated with tumor survival, therapeutic resistance, and poor prognosis through signaling pathways independent of its canonical ion channel interactions. This review summarizes the current understanding of FGF12’s non-canonical functions, highlights its emerging roles in cellular regulation, and discusses its potential mechanism in oncogenic progression. Understanding these novel functions may provide a new aspect for therapeutic targeting of FGF12 in malignancies.

Fibroblast growth factor 12 (FGF12), a member of the intracellular fibroblast growth factor homologous factor (iFGF) subfamily, has been widely studied for its role in the modulation of voltage-gated ion channels. However, recent studies suggest that FGF12 possesses various cellular functions beyond ion channel regulation, particularly in cancer progression. Accumulating evidence indicates that the upregulation of FGF12 is associated with tumor survival, therapeutic resistance, and poor prognosis through signaling pathways independent of its canonical ion channel interactions. This review summarizes the current understanding of FGF12’s non-canonical functions, highlights its emerging roles in cellular regulation, and discusses its potential mechanism in oncogenic progression. Understanding these novel functions may provide a new aspect for therapeutic targeting of FGF12 in malignancies.