BRN2 in Lineage Plasticity: A Prostate Cancer-Focused Perspective.
Lineage plasticity is a major mechanism by which prostate cancer adapts to therapeutic pressure, particularly following sustained inhibition of androgen receptor signaling. A central mediator of this process is BRN2, a POU3F2 neural lineage transcription factor that is normally suppressed in AR-dependent luminal prostate epithelium but becomes aberrantly activated during progression to castration-resistant and neuroendocrine prostate cancer. This review examines how BRN2 connects developmental neurogenesis to therapy-induced tumor reprogramming. We integrate insights from neurodevelopment and direct lineage reprogramming to describe how BRN2 maintains stem-like and neuroendocrine transcriptional states. Mechanistically, we discuss how AR suppression, cooperating oncogenic drivers, epigenetic remodeling, and post-translational modification activate BRN2 and reshape transcriptional networks involving SOX2, Wnt signaling, N-Myc, and EZH2. We also evaluate strategies to target BRN2 and its associated dependencies, including direct inhibition of BRN2 DNA binding and pharmacologic disruption of cooperating epigenetic complexes such as BRD4, EZH2, and LSD1, though EZH2 inhibition may paradoxically promote further neuroendocrine differentiation. We additionally assess BRN2 as a potential circulating biomarker, detectable in extracellular vesicles, though no clinical-grade assay has been validated. This review highlights BRN2 as a key transcriptional regulator of lineage plasticity in prostate cancer, with important implications for overcoming therapy resistance in advanced prostate cancer.