Abstract 5903: TUG1-mediated replication stress regulation as a potential vulnerability in bladder cancer

Abstract Bladder cancer (BCa) displays marked genomic instability driven by APOBEC mutational processes, recurrent alterations in TP53, RB1, ERCC2, and ATM, and chronic replication stress (RS). Such RS-rich genomes require mechanisms that buffer R-loop accumulation and replication-associated DNA damage to sustain proliferation. We have previously demonstrated that the long non-coding RNA (lncRNA) Taurine upregulated gene 1 (TUG1) is a RS-responsive lncRNA induced by ATR-CHK1 signaling and essential for maintaining genome stability across multiple cancer types. Our prior work revealed that TUG1 promotes R-loop resolution and supports tumor cell survival under genotoxic conditions. Given that BCa is intrinsically defined by APOBEC-driven mutagenesis, DNA repair defects, and persistent RS, we hypothesized that BCa cells may rely on TUG1-mediated R-loop regulation. To evaluate this possibility, we analyzed TCGA-BLCA and found significantly elevated TUG1 expression in tumor tissues compared with adjacent normal urothelium. RNA-FISH of clinical BCa specimens further confirmed higher expression of TUG1 within malignant epithelial compartments. Functional assays using a TUG1-targeting antisense oligonucleotide (TUG1-ASO) demonstrated efficient depletion of endogenous TUG1, reduced cell viability, and downregulation of cell-cycle-related transcripts. Loss of TUG1 also induced replication stress and DNA damage markers, including pRPA32 and γH2AX, and sensitized BCa cells to RS-inducing conditions.Taken together, these findings indicate that BCa cells depend on TUG1 to maintain proliferation under high RS pressure. Therapeutic depletion of TUG1 disrupts this adaptive mechanism and impairs tumor cell growth, supporting TUG1 as a potential therapeutic target in BCa. Citation Format: Akinobu Ishiyama, Miho Suzuki, Keiko Shinjo, Shusuke Akamatsu, Yutaka Kondo. TUG1-mediated replication stress regulation as a potential vulnerability in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5903.