Abstract:
Epithelial integrity is maintained through coordinated regulation of cell–cell adhesion, apico basal polarity, and transcriptional programs that preserve epithelial identity. Disruption of these processes underlies epithelial–to–mesenchymal transition (EMT), a key driver of cancer invasion and metastasis. Fibrillarin (FBL) is a conserved nucleolar protein best known for its essential role in ribosomal RNA biogenesis; however, emerging evidence suggests that its functions extend beyond ribosome assembly. Here, we identify a previously unrecognized role for FBL in safeguarding epithelial architecture by regulating chromatin-mediated control of cell polarity genes. Using colorectal (DLD-1) and breast epithelial (MCF10A[p53DN]) models, we show that FBL depletion leads to profound disruption of epithelial morphology, characterized by loss of cobblestone architecture, destabilization of adherens and tight junctions, and enhanced cell migration and invasion. Mechanistically, FBL loss induces clathrin- and dynamin-dependent internalization of E-cadherin without altering global endocytic flux, indicating selective perturbation of junctional trafficking. Transcriptomic analyses reveal significant deregulation of pathways associated with cell adhesion, apical membrane organization, and EMT, identifying the basolateral polarity regulator Scribble (SCRIB) as a key downstream effector of FBL function.We demonstrate that FBL depletion transcriptionally represses SCRIB through increased deposition of the repressive histone mark H3K27me3 at its promoter. This epigenetic silencing is driven by the relocalization of a subpopulation of EZH2, the catalytic component of Polycomb Repressive Complex 2 (PRC2), from the nucleolus to the nucleoplasm. Disruption of the FBL–EZH2 interaction, either by FBL depletion or deletion of its RNA-binding domain, enhances nucleoplasmic EZH2 occupancy at PRC2 target genes, including SCRIB, thereby promoting epithelial destabilization. Pharmacological inhibition of EZH2 restores Scribble expression, rescues E-cadherin localization, and suppresses aberrant cell migration, establishing the functional importance of nucleolar EZH2 sequestration. Prolonged FBL depletion further induces EMT in breast epithelial cells, marked by activation of Akt signaling, upregulation of mesenchymal transcription factors (Snail, Twist, and Zeb1), and loss of epithelial markers. In vivo, FBL depletion enhances tumor growth and lung metastasis in xenograft models, correlating with reduced Scribble levels and altered EZH2 localization. Collectively, these findings uncover an FBL–EZH2–Scribble regulatory axis that links nucleolar function to chromatin regulation, epithelial identity, and metastatic progression, positioning fibrillarin as a critical suppressor of EMT and a potential therapeutic vulnerability in epithelial cancers.
