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
Affiliations
Swagata Adhikari
Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India; Homi Bhabha National Institute, Mumbai, India
Vipin Singh
Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India; Homi Bhabha National Institute, Mumbai, India
Sandhik Nandi
Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India; Homi Bhabha National Institute, Mumbai, India
Manorama Ghosal
Chemical Sciences Division, Saha Institute of Nuclear Physics, HBNI, 1/AF Bidhannagar, Kolkata 700064, India; Homi Bhabha National Institute, Mumbai, India
Nidharshan Sundar Raj
National Centre for Biological Sciences, TIFR, Bangalore, India
Jayati Khanna
Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research, Pune, Maharashtra, India
Apoorva Bhattacharya
Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
Aindrila Kabiraj
Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India; Homi Bhabha National Institute, Mumbai, India
Atanu Mondal
Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India; Homi Bhabha National Institute, Mumbai, India
Madavan Vasudevan
Theomics International Pvt Ltd., Bangalore, India
Dulal Senapati
Chemical Sciences Division, Saha Institute of Nuclear Physics, HBNI, 1/AF Bidhannagar, Kolkata 700064, India; Homi Bhabha National Institute, Mumbai, India
Himansu Roy
Department of Surgery, Medical College and Hospital, Kolkata, West Bengal, India
Kundan Sengupta
Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research, Pune, Maharashtra, India
Dimple Notani
National Centre for Biological Sciences, TIFR, Bangalore, India
Chandrima Das
Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India; Homi Bhabha National Institute, Mumbai, India; Corresponding author
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.
