Leukemia inhibitory factor promotes castration-resistant prostate cancer and neuroendocrine differentiation by activated ZBTB46.

PURPOSE: The molecular targets for castration-resistant prostate cancer (CRPC) are unknown because the disease inevitably recurs, and therapeutic approaches for CRPC patients remain less well understood. We sought to investigate regulatory mechanisms that result in increased therapeutic resistance, which is associated with neuroendocrine (NE) differentiation of prostate cancer and linked to dysregulation of the androgen-responsive pathway.

EXPERIMENTAL DESIGN: The underlying intracellular mechanism that sustains the oncogenic network involved in NE differentiation and therapeutic resistance of prostate cancer was evaluated to investigate and identify effectors. Multiple sets of samples with prostate adenocarcinomas and CRPC were assessed via immunohistochemistry and other assays.

RESULTS: We demonstrated that leukemia inhibitory factor (LIF) was induced by androgen deprivation therapy (ADT) and was upregulated by ZBTB46 in prostate cancer to promote CRPC and NE differentiation. LIF was found to be induced in prostate cancer patients after ADT and was associated with enriched nuclear ZBTB46 staining in high-grade prostate tumors. In prostate cancer cells, high ZBTB46 output was responsible for the activation of LIF-signal transduction and activator of transcription 3 (STAT3) signaling and NE-like features. The abundance of LIF was mediated by ADT-induced ZBTB46 through a physical interaction with the regulatory sequence of LIF. Analysis of serum from patients showed that cases of higher tumor grade and metastatic prostate cancer exhibited higher LIF titers.

CONCLUSIONS: Our findings suggest that LIF is a potent serum biomarker for diagnosing advanced prostate cancer and that targeting the ZBTB46-LIF axis may therefore inhibit CRPC development and NE differentiation after ADT.