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UBR7 in concert with EZH2 inhibits the TGF-β signalling leading to extracellular matrix remodelling [RNA-seq]

ABSTRACT: The intricate interplay between resident cells and the extracellular matrix (ECM) wields a profound influence on cancer progression. In Triple Negative Breast Cancer (TNBC), ECM architecture evolves primarily due to the enrichment of lysyl oxidase, fibronectin, and collagen that eventually promote distant metastasis. Here, we have uncovered a pivotal transcription regulatory mechanism of the epigenetic regulator UBR7 in conjunction with histone methyltransferase EZH2 in regulating TGF-b/Smad signalling-axis thereby fine-tuning the ECM genes. Remarkably, UBR7 loss leads to a dramatic reduction in the facultative heterochromatin mark H3K27me3 in chromatin, leading to ECM genes firing. Apart from playing a seminal role in matrix deposition in adherent-cancer cells and spheroids, UBR7 alters the total collagen content and lysyl oxidase activity thereby directly impacting the matrix stiffness and consequently its invasive properties. These results can be further translated to TNBC-patients, where reduced RNA/protein levels of UBR7 is accompanied by heightened expression of the ECM-components and their functional-activity which is responsible for fibrosis-mediated matrix stiffness. Thus, UBR7 acts as a master regulator of TNBC matrix-stiffening thereby impacting its metastatic potential.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262488 | GEO | 2025/03/26

REPOSITORIES: GEO

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Project description:To further examine the gene expression of isolated primary mouse proximal tubular epithelial cells (mPTECs) during ex vivo culture, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish the key regulatory transcription factor which was significantly altered. Primary culuture of mPTECs were cultured on culture dishes for 1 and 3 days. As compared to freshly isolated mPTECs, a 1801-gene consensus signature was identified that distinguished between day 1 and and day 3 samples. Within these genes, 78 transcriptal factors were dramatically altered. Expression of three genes (KLF5, KLF4, and CCND1) from this signature was quantified in the same RNA samples by RT-PCR. The proliferation of mouse proximal tubular epithelial cells in ex vivo culture depends on matrix stiffness. Combined analysis of the microarray and experimental data revealed that Krüppel-like factor 5 (Klf5) was the most upregulated transcription factor accompanied by Krüppel-like factor 4 (Klf4) downregulation when cells on stiff matrix. These changes were reversed by soft matrix via ERK inactivation. Knockdown of Klf5 or forced-expression of Klf4 inhibited stiff matrix-induced cell spreading and proliferation, suggesting that Klf5/Klf4 act as positive/negative regulators, respectively. Moreover, stiff matrix-activated ERK increased the protein level and nuclear translocation of mechanosensitive Yes-associated protein 1 (YAP1), which is reported to prevent Klf5 degradation. Finally, in vivo model of unilateral ureteral obstruction (UUO) revealed that matrix stiffness-regulated Klf5/Klf4 is related to the pathogenesis of renal fibrosis. In the dilated tubules of obstructed kidney, ERK/YAP1/Klf5/Cyclin D1 axis were upregulated and Klf4 was downregulated. Inhibition of collagen crosslinking by lysyl oxidase inhibitor alleviated UUO-induced tubular dilatation and proliferation with preserving Klf4 and suppressing the ERK/YAP1/Klf5/Cyclin D1 axis. This study unravels a novel mechanism how matrix stiffness regulates cellular proliferation and highlights the importance of matrix stiffness-modulated Klf5/Klf4 in the regulation of renal physiological functions and fibrosis progression. Gene expression in cultured mPTECs was measured at 0, 1 and 3 days after culturing on culture dishes.

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UBR7 in concert with EZH2 inhibits the TGF-β signalling leading to extracellular matrix remodelling [RNA-seq]

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