Cell Reports (Jul 2024)

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

  • Swagata Adhikari,
  • Vipin Singh,
  • Sandhik Nandi,
  • Manorama Ghosal,
  • Nidharshan Sundar Raj,
  • Jayati Khanna,
  • Apoorva Bhattacharya,
  • Aindrila Kabiraj,
  • Atanu Mondal,
  • Madavan Vasudevan,
  • Dulal Senapati,
  • Himansu Roy,
  • Kundan Sengupta,
  • Dimple Notani,
  • Chandrima Das

Journal volume & issue
Vol. 43, no. 7
p. 114394

Abstract

Read online

Summary: 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.

Keywords