PLK1-OCT4调控轴控制前列腺癌的谱系可塑性和神经内分泌分化

Prostate cancer remains the most frequently diagnosed malignancy and a major cause of cancer-related death among men in the United States. A particularly aggressive subtype, neuroendocrine prostate cancer (NEPC), often emerges as a treatment-induced state in patients receiving prolonged second-generation anti-androgen therapies. NEPC tumors progress rapidly, respond poorly to conventional treatments, and are associated with markedly worse outcomes. This therapy-driven lineage switch highlights the need to define the molecular mechanisms governing neuroendocrine transformation and identify actionable vulnerabilities. PLK1 (Polo-like kinase 1) is a key regulator of mitosis and has been increasingly linked to prostate cancer progression. Our work identifies OCT4, a core pluripotency transcription factor, as a novel PLK1 substrate. We demonstrate that PLK1 phosphorylates OCT4 and promotes its degradation. In CRPC cells, short-term enzalutamide treatment elevates both stemness and neuroendocrine markers; however, with prolonged exposure, stemness features decline while neuroendocrine markers remain elevated, suggesting a transition from a transient stem-like state to a stable NEPC phenotype. We observed a similar plasticity pattern in 16D cells treated with enzalutamide, and in a DOX-inducible LNCaP Rb/p53 knockdown model, where DOX induction likewise promoted a shift toward neuroendocrine features. In N2P1 as a NEPC cells, knockdown or degradation of OCT4 further increased MYC and neuroendocrine markers, emphasizing OCT4's role in lineage balance and tumor plasticity. RNA-sequencing of N2P1 cells revealed significant elevation of MYC and BRD2, a BET-family chromatin regulator associated with MYC transcriptional control. Increased BRD2 expression, combined with enhanced MYC signaling, prompted us to investigate whether dual inhibition of PLK1 and BET proteins could more effectively suppress NEPC growth. To test this, we performed in vivo xenograft studies using pre-castrated NSG mice bearing N2P1 tumors and treated animals with vehicle, the PLK1 inhibitor Onvansertib, the BET inhibitor AZD5153, or the combination. Both single agents reduced tumor growth, but the combination therapy produced the most robust and sustained suppression, suggesting a synergistic effect and supporting co-targeting of PLK1 signaling and BET-driven chromatin regulation. Collectively, our findings reveal a critical role for the PLK1-OCT4 axis in prostate cancer plasticity and neuroendocrine differentiation. These results support a therapeutic strategy that simultaneously inhibits PLK1 and BET proteins as a promising approach to slow NEPC progression and improve patient outcomes.