Leukemia Inhibitory Factor Promotes Castration-resistant Prostate Cancer and Neuroendocrine Differentiation by Activated ZBTB46

Yen-Nien Liu, Shaoxi Niu, Wei-Yu Chen, Qingfu Zhang, Yulei Tao, Wei-Hao Chen, Kuo-Ching Jiang, Xufeng Chen, Huaiyin Shi, Aijun Liu, Jinhang Li, Yanjing Li, Yi-Chao Lee, Xu Zhang, Jiaoti Huang

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


Purpose: The molecular targets for castration-resistant prostate cancer (CRPC) are unknown because the disease inevitably recurs, and therapeutic approaches for patients with CRPC remain less well understood. We sought to investigate regulatory mechanisms that result in increased therapeutic resistance, which is associated with neuroendocrine 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 neuroendocrine 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 IHC 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 CRPCand neuroendocrine differentiation. LIF was found to be induced in patients with prostate cancer after ADT and was associated with enriched nuclear ZBTB46 staining in highgrade prostate tumors. In prostate cancer cells, high ZBTB46 output was responsible for the activation of LIF-STAT3 signaling and neuroendocrine-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 neuroendocrine differentiation after ADT.

Original languageEnglish
Pages (from-to)4128-4140
Number of pages13
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Issue number13
Early online dateApr 8 2019
Publication statusPublished - 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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