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Cellular and Molecular Biology

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

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.

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Fig. 1: LIF signalling enhances ZBTB46-driven glucose metabolism of PCa.
Fig. 2: PCK1 is upregulated by LIF/ZBTB46 in PCa cells.
Fig. 3: ADT increased PCK1 expression, which promotes NE differentiation of PCa cells through LIF/ZBTB46 signalling upregulation.
Fig. 4: PCK1 and LIF upregulate ZBTB46, and ZBTB46 directly binds CHGA, ENO2, and SYP regulatory sequences.
Fig. 5: PCK1 upregulation is associated with NE-differentiated PCa.
Fig. 6: Target PCK1 reduces tumour growth of AR-negative and ADT-resistant PCa cells.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr Hsing-Jien Kung (Academician of the Academia Sinica, Chair Professor of Taipei Medical University) for reading the manuscript and providing comments and helpful suggestions. This work was jointly supported by grants from the Ministry of Science and Technology, Taiwan (MOST109-2326-B-038-001-MY3 and MOST110-2622-B-038-002 to Y-NL, and MOST109-2314-B-038-105 to Y-CW), the Taipei Medical University-Chi Mei Medical Center (110CM-TMU-07 to Y-NL), and the Higher Education Sprout Project by the Ministry of Education (MOE).

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Authors

Contributions

W-YC and Y-NL designed the experiments and supervised the project. Y-CW, C-LL, H-LY, W-HC, K-CJ, and VTNT performed the experiments. Y-CW, W-YC, and JH provided the human PCa samples. W-YC performed the histomorphometric analysis. H-LY constructed the databases and performed the statistical and computational analyses. MH provided assistance with animal experiments. Y-CW, C-LL, W-YC, and Y-NL wrote, reviewed, and/or revised the manuscript. All authors analysed and interpreted the data.

Corresponding authors

Correspondence to Wei-Yu Chen or Yen-Nien Liu.

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Ethics approval and consent to participate

CRPC and SCPC TMAs were obtained from Duke University School of Medicine, and their use was approved by the Duke University School of Medicine Institutional Review Board (protocol ID: Pro00070193). PCa tissue samples before and after ADT were collected from Taipei Medicine University-Wan-Fang Hospital (Taipei, Taiwan), the collection of which followed the Declaration of Helsinki and was approved by the Taipei Medical University Joint Institutional Review Board (protocol ID: N202103136). Protocols of in vivo experiment was followed “Guideline for the Care and Use of Laboratory Animals” published by Council of Agriculture and approved by Taipei Medical University Institutional Animal Care and Use Committee (approval ID LAC-2021-0111).

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Not applicable.

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The authors declare no competing interests.

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Wen, YC., Liu, CL., Yeh, HL. et al. PCK1 regulates neuroendocrine differentiation in a positive feedback loop of LIF/ZBTB46 signalling in castration-resistant prostate cancer. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01631-3

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