ASCL1-mediated ferroptosis resistance enhances the progress of castration-resistant prostate cancer to neurosecretory prostate cancer

Neuroendocrine prostate cancer (NEPC) is a multi-resistant variant of prostate cancer (PCa) that frequently emerges in castration-resistant prostate cancer (CRPC). NEPC is usually associated with tumor aggression, hormone therapy resistance, and poor clinical outcome. However, the mechanisms underlying the trans-differentiation from CRPC to NEPC have not been elucidated. Achaete-scute complex-like 1 (ASCL1) plays a role in neuronal commitment and differentiation and olfactory and autonomic neuron generation. This study revealed that ASCL1 was regulated by the SRY-box transcription factor 2 (SOX2) and highly expressed in NEPC cells, which was closely related to poor prognosis. Moreover, ASCL1 overexpression significantly enhanced CRPC progression to NEPC by resisting ferroptosis. Mechanically, ferroptosis resistance was mediated by CAMP-responsive element binding protein 1 (CREB1) phosphorylation, promoted by substantially upregulated ASCL1 in NEPC cells. In addition, upregulated SOX2 induced PCa cell differentiation into neuroendocrine tumors by mediating their lineage changes. In conclusion, inhibiting the ferroptosis resistance mediated by ASCL1 could provide a new NEPC therapeutic target and increase patient survival.