Bladder cancer (BLCA) is a global malignancy characterized by its widespread prevalence, adverse clinical prognosis, and recurrent nature. Deciphering the molecular intricacies driving BLCA progression is crucial for devising effective treatments and improving survival rates [1]. In this pursuit, our study sheds light on the significant role of DLGAP5 as an oncogene in BLCA, providing compelling evidence that highlights its heightened expression in BLCA and its robust correlation with poor prognosis.

After high-throughput sequencing of clinical BLCA tissues and normal bladder tissues, we revealed a striking increase in DLGAP5 expression in BLCA tissues. This discovery propelled us to further investigate the molecular mechanisms governed by DLGAP5 in the context of BLCA. Also recognized as KIAA0008, DLG7, and HURP, DLGAP5 plays a pivotal role in the spindle assembly pathway, is regulated by Ran-importin β, and contributes to chromosome segregation during mitosis [2]. Despite these known functions, limited research has explored DLGAP5 and its involvement in tumorigenesis.

Our comprehensive in vitro and in vivo experiments revealed the substantial impact of alterations in DLGAP5 expression on both cell proliferation and migration, underscoring its critical role in BLCA development. Mechanistically, our findings elucidated DLGAP5 as a direct binding partner of E2F1 that plays a crucial role in stabilizing E2F1 by impeding its ubiquitination through USP11. Adding another layer to the complexity, E2F1, a pivotal transcription factor, was found to foster the transcription of DLGAP5, establishing a positive feedback loop between the two entities and thereby accelerating BLCA progression.

In essence, our study identified DLGAP5 as a noteworthy oncogene in BLCA, revealing a novel mechanism that fuels disease development. In addition to its role as a diagnostic marker, DLGAP5 has emerged as a potential therapeutic target for mitigating the impact of BLCA.

A schematic model of the DLGAP5/USP11-E2F1 feedback loop promoting BLCA progression. DLGAP5 facilitates E2F1 protein stability through the deubiquitinating enzyme USP11, which prevents E2F1 ubiquitination. Additionally, E2F1 enhances DLGAP5 transcription by binding to its promoter region.

Dr. Lingao Ju and Dr. Xinghuan Wang are the corresponding authors of this paper, with Dr. Fenfang Zhou, PhD candidate Zhao Deng and Dr. Dexin Shen serving as co-first authors.

References

1. van Hoogstraten LMC, Vrieling A, van der Heijden AG, Kogevinas M, Richters A, Kiemeney LA. Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice. Nat Rev Clin Oncol. 2023;20(5):287-304. doi:10.1038/s41571-023-00744-3
2. Silljé HH, Nagel S, Körner R, Nigg EA. HURP is a Ran-importin beta-regulated protein that stabilizes kinetochore microtubules in the vicinity of chromosomes. Curr Biol. 2006;16(8):731-742. doi:10.1016/j.cub.2006.02.070.