Journal Article

STAG2 cohesin cooperates with DREAM to maintain quiescence and suppress tumourigenesis in the urothelium

Ramal, Maria, Marti-Renom, Marc A, Arbonés, Maria L, Xu, Jianming, Novillo-Font, Meritxell, Kalisz, Mark, Lapi, Eleonora, Radvanyi, François, Zarzuela, Eduardo, Real, Francisco X, Barallobre, María J, Isasa, Marta, Graña-Castro, Osvaldo, Martínez-Torrecuadrada, Jorge L, Martínez de Villarreal, Jaime, Bernard-Pierrot, Isabelle, Marqués, Miriam, Marti-Marimon, Maria, Cayuela, Ana, Novell, Mireia

2025

Overview

The maintenance of quiescence is essential for tissue homeostasis. is one of the few genes mutated in the normal urothelium of organ donors, with mutant cells undergoing positive selection . is also a major tumour suppressor gene and its inactivation is an early event in bladder carcinogenesis . However, how STAG2, a cohesin component, regulates urothelial homeostasis remains largely unknown. Here, we demonstrate that inactivation in normal murine urothelial cells interferes with differentiation programs, triggers transient cell cycle entry, and primes cells for clonal expansion under stress. Moreover, STAG2 loss enhances tumor formation in urothelial cells expressing mutant - the key oncogene in bladder cancer . We reveal that STAG2 cooperates with the DREAM transcriptional complex, a master regulator of quiescence , by binding to shared genomic sites, including cell cycle control genes. STAG2 loss alters DREAM target expression, complex composition, and chromatin distribution, and leads to rewiring of chromatin interactions involving DREAM binding motifs in genes critical for cell cycle entry. Our findings provide compelling evidence that STAG2 loss disrupts in 3D genome organization through a novel mechanism involving the DREAM complex, thereby impairing homeostatic quiescence and increasing oncogenic sensitivity.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Cancer Biology