Fibrillarin regulates epithelial integrity via EZH2-mediated modulation of scribble expression

Abstract

Fibrillarin (FBL) is a nucleolar protein critical for rRNA biogenesis. We show that FBL is essential for the maintenance of epithelial integrity through its regulation of cell-cell adhesion proteins. RNA-seq analyses upon FBL depletion revealed deregulation of adhesion- and apical membrane organization-associated pathways. FBL loss deregulates cell polarity via increased deposition of H3K27me3 on the SCRIB promoter, driven by the localization of a subpopulation of EZH2 from the nucleolus to the nucleoplasm. Disrupting the FBL-EZH2 interaction increases cell migration, underscoring a requirement for retaining EZH2 also in the nucleolus. Furthermore, FBL depletion induces EMT in breast epithelial cells, owing to increased levels of mesenchymal factors (Snail1, Twist1, and Zeb1) and activation of Akt. Since Scribble tethers PHLPP1 and PTEN to antagonize Akt, repression of Scribble induces EMT. In summary, FBL safeguards epithelial integrity, by regulating the expression of Scribble, uncovering an FBL-EZH2 axis in EMT and metastasis.