UBR7 in concert with EZH2 inhibits the TGF-β signaling leading to extracellular matrix remodeling

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. [Display omitted] •UBR7 is a regulator of TGF-β/SMAD signaling axis•UBR7 interacts with EZH2 to maintain H3K27me3 mark on chromatin•UBR7 in concert with EZH2 suppresses TGFB1 gene, thereby affecting ECM gene transcription•UBR7 impairs matrix stiffness, affecting the TNBC invasion in vivo Adhikari et al. demonstrate that epigenetic regulator UBR7 functions in concert with EZH2 to modulate TGF-β signaling cascade by altering H3K27me3 landscape, thereby affecting the transcription of extracellular matrix genes. Thus, UBR7 plays a key role in stiffness-mediated metastasis suppression in triple-negative breast cancer.