PCK1 regulates neuroendocrine differentiation in a positive feedback loop of LIF/ZBTB46 signalling in castration-resistant prostate cancer

Yu Ching Wen, Chien Liang Liu, Hsiu Lien Yeh, Wei Hao Chen, Kuo Ching Jiang, Van Thi Ngoc Tram, Michael Hsiao, Jiaoti Huang, Wei Yu Chen, Yen Nien Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Castration-resistant prostate cancer (CRPC) patients frequently develop neuroendocrine differentiation, with high mortality and no effective treatment. However, the regulatory mechanism that connects neuroendocrine differentiation and metabolic adaptation in response to therapeutic resistance of prostate cancer remain to be unravelled. Methods: By unbiased cross-correlation between RNA-sequencing, database signatures, and ChIP analysis, combining in vitro cell lines and in vivo animal models, we identified that PCK1 is a pivotal regulator in therapy-induced neuroendocrine differentiation of prostate cancer through a LIF/ZBTB46-driven glucose metabolism pathway. Results: Upregulation of PCK1 supports cell proliferation and reciprocally increases ZBTB46 levels to promote the expression of neuroendocrine markers that are conducive to the development of neuroendocrine characteristic CRPC. PCK1 and neuroendocrine marker expressions are regulated by the ZBTB46 transcription factor upon activation of LIF signalling. Targeting PCK1 can reduce the neuroendocrine phenotype and decrease the growth of prostate cancer cells in vitro and in vivo. Conclusion: Our study uncovers LIF/ZBTB46 signalling activation as a key mechanism for upregulating PCK1-driven glucose metabolism and neuroendocrine differentiation of CRPC, which may yield significant improvements in prostate cancer treatment after ADT using PCK1 inhibitors.

Original languageEnglish
Pages (from-to)778-790
Number of pages13
JournalBritish Journal of Cancer
Volume126
Issue number5
DOIs
Publication statusPublished - Mar 23 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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