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

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

  • Br J Cancer. 2022 Mar;126(5):778-790. doi: 10.1038/s41416-021-01631-3.
Yu-Ching Wen  # 1 2 3,  Chien-Liang Liu  # 4,  Hsiu-Lien Yeh 5,  Wei-Hao Chen 6,  Kuo-Ching Jiang 6,  Van Thi Ngoc Tram 6,  Michael Hsiao 7,  Jiaoti Huang 8,  Wei-Yu Chen 9 10,  Yen-Nien Liu 11
Affiliations

Affiliations

  • 1 Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 2 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 TMU Research Center of Urology and Kidney, Taipei medical university, Taipei, Taiwan.
  • 4 Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.
  • 5 General Education Development Center, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan.
  • 6 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 7 Genomics Research Center, Academia Sinica, Taipei, Taiwan.
  • 8 Department of Pathology, Duke University Medical Center, Durham, NC, USA.
  • 9 Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 10 Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 11 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. [email protected].
  • # Contributed equally.
PMID: 34815524 DOI: 10.1038/s41416-021-01631-3
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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