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

ABSTRACT: Phenotypic switching is an emerging driver of cancer treatment resistance, yet early signals regulating this process remain unclear. Here, using longitudinal single-cell RNA sequencing, we mapped differentiation trajectories in the LTL331 prostate adenocarcinoma patient-derived xenograft (PDX) model undergoing neuroendocrine prostate cancer (NEPC) transformation post castration. Our analyses identified a key differentiation node marked by epithelial-mesenchymal transition (EMT) and repressor element-1 silencing transcription factor (REST) downregulation driven by the CXCR4-LASP1-G9a-SNAIL axis. Mechanistically, CXCR4 activation promotes nuclear translocation of LASP1 that links G9a and SNAIL via SH3/proline-rich motif and LIM/SNAG domain interactions, enabling SNAIL-mediated REST repressio

SUBMITTER: Liu L 

PROVIDER: S-EPMC12366657 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature