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

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.