Abstract 1422: STAG2-mediated gene expression programs promote invasion in muscle invasive bladder cancer

Abstract Stromal antigen 2 (STAG2) is associated with worse overall and progression free survival of muscle invasive bladder cancer (MIBC) patients. Furthermore, STAG2 expression is associated with motility and invasiveness of MIBC cell in vitro, suggesting that STAG2 acts as an oncogene in MIBC. In normal cells, STAG2 assists with sister chromatid cohesion, DNA damage repair, and maintenance of genome organization as part of the cohesin complex. However, mechanisms underlying the pro-oncogenic function of STAG2 in MIBC remain unknown. After knockdown of STAG2 in T24 MIBC cells, thousands of genes are differentially expressed. Given this data and the established role of STAG2 genome organization, we hypothesized that STAG2 exerts a pro-oncogenic function through regulating expression of invasion-related genes. To identify target genes, we utilized chromatin immunoprecipitation (ChIP) followed by sequencing and qPCR. From these, we identified the cholesterol efflux pump ABCA1 as a direct STAG2 target gene, which is significantly downregulated after STAG2 knock out (KO). ABCA1 overexpression is associated with invasion of melanoma and colorectal cancer cells, and therefore we hypothesized that STAG2 mediated ABCA1 expression may enforce an invasive phenotype in MIBC cells. To assess the mechanism of ABCA1 regulation, we investigated possible co-regulators and found that in the absence of STAG2, the co-repressor TRIM28 becomes enriched at the ABCA1 promoter. This suggests that STAG2 and TRIM28 may compete to regulate expression of ABCA1, where STAG2 promotes and TRIM28 represses ABCA1 transcription. In support of this, analysis of patient transcriptome data demonstrates that patients with upper quartile STAG2 expression or lowest quartile TRIM28 expression have significantly higher ABCA1 expression. To further query how loss of STAG2 downregulates ABCA1, we analyzed the histone landscape at the ABCA1 promoter region by ChIP-qPCR. Results show that STAG2 KO is associated with decreased H3K4 and H3K27 acetylation, which are typically associated with active gene promoters. Altogether, these results suggest that STAG2 promotes invasion by enforcing expression of ABCA1, which is achieved through displacement of TRIM28 and a subsequent decrease in histone acetylation. This work lays the foundation for investigation of ABCA1 as a targetable molecule in STAG2-high MIBC - for which novel therapies are critically needed. Citation Format: Sarah R. Athans, Nithya Krishnan, Swathi Ramakrishnan, Aimee Stablewski, Sofía Lage-Vickers, Geraldine Gueron, Zara Kazmierczak, Anna Woloszynska. STAG2-mediated gene expression programs promote invasion in muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1422.