Targeting the KAT8/YEATS4 Axis Represses Tumor Growth and Increases Cisplatin Sensitivity in Bladder Cancer
Bladder cancer (BC) is one of the most common malignancies, known for its high relapse rate and lack of targeted therapies. In this study, we report that YEATS domain-containing protein 4 (YEATS4) is a crucial gene for BC cell viability, as identified through CRISPR-Cas9 library screening. Additionally, we show that HUWE1, an E3 ubiquitin ligase, mediates the ubiquitination and proteasomal degradation of YEATS4, as revealed by a Protein Stability Regulators Screening Assay. KAT8, a histone acetyltransferase, acetylates YEATS4, which disrupts its interaction with HUWE1, preventing its ubiquitination and degradation. We also find that the protein levels of YEATS4 and KAT8 are positively correlated, and elevated levels of both proteins are associated with poor overall survival in BC patients. Notably, inhibiting YEATS4 acetylation with the KAT8 inhibitor MG149 reduced YEATS4 acetylation, decreased cell viability, and enhanced the sensitivity of BC cells to cisplatin treatment. These findings highlight the critical role of the KAT8/YEATS4 axis in regulating tumor growth and cisplatin sensitivity in BC cells, suggesting a potential new therapeutic strategy for BC patients.