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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wen, Y-C; Liu, C-L; Yeh, H-L; Chen, W-H; Jiang, K-C; Tram, VTN; Hsiao, M; Huang, J; Chen, W-Y; Liu, Y-N

Published Date

  • March 2022

Published In

Volume / Issue

  • 126 / 5

Start / End Page

  • 778 - 790

PubMed ID

  • 34815524

Pubmed Central ID

  • PMC8888753

Electronic International Standard Serial Number (EISSN)

  • 1532-1827

Digital Object Identifier (DOI)

  • 10.1038/s41416-021-01631-3

Language

  • eng

Conference Location

  • England