RepID orchestrates CDH1 and CTNNB1 homeostasis to regulate metastatic potential in small cell lung cancer.

Abstract

Small cell lung cancer (SCLC) is defined by its aggressive progression and early systemic dissemination, yet the molecular drivers that orchestrate its metastatic potential remain elusive. Here, we identify the replication initiation determinant protein (RepID), a chromatin-associated receptor for the CRL4 ubiquitin ligase complex, as a critical suppressor of the metastatic potential in SCLC. Analysis of patient-derived datasets revealed that RepID expression is significantly attenuated in metastatic tumors, correlating with poor clinical outcomes. Utilizing CRISPR-Cas9-mediated depletion, we demonstrate that RepID deficiency induces a profound phenotypic shift toward a spindle-like morphology, characterized by increased cellular polarity, cytoskeletal reorganization, and markedly enhanced migratory and invasive capacities in vitro. Mechanistically, RepID exerts dual-level control over epithelial homeostasis by maintaining CDH1 transcription through an ETS1-dependent axis, while simultaneously stabilizing the CTNNB1 protein. We find that loss of RepID triggers an aberrant surge in CUL1 abundance and neddylation, thereby accelerating CRL1-mediated ubiquitination and proteasomal degradation of CTNNB1. This RepID-dependent proteostatic control is reversible via inhibition of the neddylation or proteasome pathways, and re-expression of RepID effectively rescues cellular adhesion and attenuates invasive traits. Our findings establish RepID as a previously unrecognized molecular rheostat that constrains SCLC metastatic potential by integrating transcriptional regulation of epithelial integrity with post-translational control of the CRL1-CTNNB1 axis, providing a potential therapeutic vulnerability in recalcitrant SCLC.