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

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• Fibrillarin (FBL) is a crucial nucleolar protein involved in rRNA biogenesis.
• Epithelial integrity is vital for tissue function and is maintained by cell-cell adhesion and polarity.
• Epithelial-mesenchymal transition (EMT) is a process implicated in cancer metastasis.

Purpose of the Study:

• To investigate the role of Fibrillarin (FBL) in maintaining epithelial integrity.
• To elucidate the molecular mechanisms by which FBL regulates cell adhesion and polarity.
• To explore the connection between FBL, EZH2, and EMT in breast epithelial cells.

Main Methods:

• RNA sequencing (RNA-seq) was performed upon FBL depletion.
• Chromatin immunoprecipitation (ChIP) assays were used to assess H3K27me3 deposition.
• Western blotting and immunofluorescence were employed to analyze protein levels and localization.

Main Results:

• FBL depletion led to deregulation of adhesion and apical membrane organization pathways.
• FBL loss caused increased H3K27me3 on the SCRIB promoter due to EZH2 nucleolar-to-nucleoplasmic translocation.
• FBL depletion induced EMT by repressing Scribble, increasing mesenchymal factors, and activating Akt.

Conclusions:

• Fibrillarin (FBL) is essential for maintaining epithelial integrity through regulation of cell-cell adhesion proteins like Scribble.
• An FBL-EZH2 axis in the nucleolus regulates SCRIB expression and controls epithelial polarity and EMT.
• FBL's role in safeguarding epithelial integrity highlights its potential as a therapeutic target in metastasis.