@article {162687, title = {Fibrillarin regulates epithelial integrity via EZH2-mediated modulation of scribble expression.}, journal = {Cell Rep}, volume = {44}, year = {2025}, month = {2025 Nov 25}, pages = {116608}, 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.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2025.116608}, author = {Saha, Santam and A K, Balaji and Meel, Sweety and Notani, Dimple and Sengupta, Kundan} } @article {145426, title = {UBR7 in concert with EZH2 inhibits the TGF-β signaling leading to extracellular matrix remodeling.}, journal = {Cell Rep}, volume = {43}, year = {2024}, month = {2024 Jun 25}, pages = {114394}, abstract = {

The intricate interplay between resident cells and the extracellular matrix (ECM) profoundly influences cancer progression. In triple-negative breast cancer (TNBC), ECM architecture evolves due to the enrichment of lysyl oxidase, fibronectin, and collagen, promoting distant metastasis. Here we uncover a pivotal transcription regulatory mechanism involving the epigenetic regulator UBR7 and histone methyltransferase EZH2 in regulating transforming growth factor (TGF)-β/Smad signaling, affecting the expression of ECM genes. UBR7 loss leads to a dramatic reduction in facultative heterochromatin mark H3K27me3, activating ECM genes. UBR7 plays a crucial role in matrix deposition in adherent cancer cells and spheroids, altering collagen content and lysyl oxidase activity, directly affecting matrix stiffness and invasiveness. These findings are further validated in\ vivo in mice models and TNBC patients, where reduced UBR7 levels are accompanied by increased ECM component expression and activity, leading to fibrosis-mediated matrix stiffness. Thus, UBR7 is a master regulator of matrix stiffening, influencing the metastatic potential of TNBC.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2024.114394}, author = {Adhikari, Swagata and Singh, Vipin and Nandi, Sandhik and Ghosal, Manorama and Raj, Nidharshan Sundar and Khanna, Jayati and Bhattacharya, Apoorva and Kabiraj, Aindrila and Mondal, Atanu and Vasudevan, Madavan and Senapati, Dulal and Roy, Himansu and Sengupta, Kundan and Notani, Dimple and Das, Chandrima} } @article {82356, title = {Twist1 induces chromosomal instability (CIN) in colorectal cancer cells.}, journal = {Hum Mol Genet}, volume = {29}, year = {2020}, month = {2020 Jun 27}, pages = {1673-1688}, abstract = {

Twist1 is a basic helix-loop-helix transcription factor, essential during early development in mammals. While Twist1 induces epithelial-to-mesenchymal transition (EMT), here we show that Twist1 overexpression enhances nuclear and mitotic aberrations. This is accompanied by an increase in whole chromosomal copy number gains and losses, underscoring the role of Twist1 in inducing chromosomal instability (CIN) in colorectal cancer cells. Array comparative genomic hybridization (array CGH) analysis further shows sub-chromosomal deletions, consistent with an increased frequency of DNA double strand breaks (DSBs). Remarkably, Twist1 overexpression downmodulates key cell cycle checkpoint factors-Bub1, BubR1, Mad1 and Mad2-that regulate CIN. Mathematical simulations using the RACIPE tool show a negative correlation of Twist1 with E-cadherin and BubR1. Data analyses of gene expression profiles of patient samples from The Cancer Genome Atlas (TCGA) reveal a positive correlation between Twist1 and mesenchymal genes across cancers, whereas the correlation of TWIST1 with CIN and DSB genes is cancer subtype-specific. Taken together, these studies highlight the mechanistic involvement of Twist1 in the deregulation of factors that maintain genome stability during EMT in colorectal cancer cells. Twist1 overexpression enhances genome instability in the context of EMT that further contributes to cellular heterogeneity. In addition, these studies imply that Twist1 downmodulates nuclear lamins that further alter spatiotemporal organization of the cancer genome and epigenome. Notwithstanding their genetic background, colorectal cancer cells nevertheless maintain their overall ploidy, while the downstream effects of Twist1 enhance CIN and DNA damage enriching for sub-populations of aggressive cancer cells.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddaa076}, author = {Khot, Maithilee and Sreekumar, Dyuthi and Jahagirdar, Sanika and Kulkarni, Apoorva and Hari, Kishore and Faseela, Elangoli Ebrahimkutty and Sabarinathan, Radhakrishnan and Jolly, Mohit Kumar and Sengupta, Kundan} }