STAG2 Expression is Associated with Adverse Survival Outcomes and Regulates Cell Phenotype in Muscle-invasive Bladder Cancer

Abstract

STAG2 (Stromal Antigen 2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n=119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n=346) revealed that decreased STAG2 protein expression is associated with improved overall and progression-free survival for MIBC patients. In mouse xenograft studies, STAG2 knockdown (KD) decelerated MIBC tumor growth, whereas STAG2 overexpression accelerated tumor growth. In cell line studies, STAG2 loss augmented treatment with cisplatin, a first-line therapy for MIBC. STAG2 KD or overexpression did not alter degree of aneuploidy, copy number variations, or cell cycle distribution. However, unbiased RNA sequencing analysis revealed that STAG2 KD altered gene expression. STAG2 KD led to significant downregulation of several gene sets, such as collagen containing extracellular matrix, external encapsulating structure organization, and regulation of chemotaxis. Therefore, we investigated the effect of STAG2 KD on cell migration and invasion in vitro. We found that STAG2 KD minimized cell speed, displacement, and invasion. Altogether, our results present a non-canonical function of STAG2 in promoting cell motility and invasion of MIBC cells. This work forms the basis for additional investigation into the role of STAG2 in transcriptional regulation and how it becomes dysregulated in STAG2-mutant MIBC.

Circular STAG2 RNA Modulates Bladder Cancer Progression via miR-145-5p/TAGLN2 and Is Considered as a Biomarker for Recurrence

“…Manipulation of circSTAG2 (16)(17)(18)(19)(20)(21)(22)(23)(24)(25) expression in BCa cells showed direct dependency of cells behavior on circSTAG2(16-25) levels. It was previously shown that STAG2 downregulation in T24 cells induced elevation of invasion but not motility [39]. CircSTAG2 (16)(17)(18)(19)(20)(21)(22)(23)(24)(25) regulates at least partly both mechanisms, using different signaling pathways.…”

The consequences of cohesin mutations in myeloid malignancies

“…Another cohort consisting of 367 adults with MDS/MPN concluded that patients with STAG2 mutations had much shorter overall survival ( Palomo et al, 2020 ). Lower survival is not exclusive to MDS and a study consisting of 119 samples indicated that the overexpression of STAG2 is linked to lower survival in muscle invasive bladder cancer ( Athans et al, 2023 ).…”