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CXCR4-LASP1-G9a-SNAIL axis drives NEPC transdifferentiation via induction of EMT and downregulation of REST

Liangliang Liu1, Itzel Astiazarán Rascón2, Dong Lin3

  • 1Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.

Cell Genomics
|June 11, 2025
PubMed

Insights

Early signals driving cancer treatment resistance in prostate cancer are revealed. The CXCR4-LASP1-G9a-SNAIL axis regulates neuroendocrine prostate cancer (NEPC) transformation, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Phenotypic switching contributes to cancer treatment resistance.
  • Early regulatory signals for this process in prostate cancer are not well understood.

Purpose of the Study:

  • To identify early signals regulating phenotypic switching in prostate cancer.
  • To elucidate the mechanism of neuroendocrine prostate cancer (NEPC) transformation.

Main Methods:

  • Longitudinal single-cell RNA sequencing of a prostate adenocarcinoma patient-derived xenograft (PDX) model.
  • Analysis of differentiation trajectories during castration-induced NEPC transformation.
  • Investigation of the CXCR4-LASP1-G9a-SNAIL signaling axis.

Main Results:

  • A key differentiation node involving epithelial-mesenchymal transition (EMT) and repressor element-1 silencing transcription factor (REST) downregulation was identified.
  • The CXCR4-LASP1-G9a-SNAIL axis was found to drive NEPC transformation by repressing REST.
  • Inhibition of CXCR4 or G9a reversed NEPC cells towards an androgen receptor-active phenotype.
  • CXCR4-targeted radioligands demonstrated in vivo imaging and therapeutic potential against NEPC tumors.

Conclusions:

  • The CXCR4-LASP1-G9a-SNAIL axis is a critical regulator of epigenetic and transcriptional reprogramming during NEPC transdifferentiation.
  • Targeting this axis offers a promising therapeutic strategy for aggressive NEPC.
Keywords:
CXCR4G9a histone methyl transferaseLASP1SNAILcellular plasticityepigenetic reprogrammingneuroendocrine prostate cancerpatient-derived xenograft modelsradiotherapytargeted therapeutictransdifferentiation

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