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Published on: February 6, 2015
Targeting the KAT8/YEATS4 Axis Represses Tumor Growth and Increases Cisplatin Sensitivity in Bladder Cancer
Miner Xie1,2, Liwen Zhou1, Ting Li1
1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
Abstract:
Bladder cancer (BC) is one of the most common tumors characterized by a high rate of relapse and a lack of targeted therapy. Here, YEATS domain-containing protein 4 (YEATS4) is an essential gene for BC cell viability using CRISPR-Cas9 library screening is reported, and that HUWE1 is an E3 ligase responsible for YEATS4 ubiquitination and proteasomal degradation by the Protein Stability Regulators Screening Assay. KAT8-mediated acetylation of YEATS4 impaired its interaction with HUWE1 and consequently prevented its ubiquitination and degradation. The protein levels of YEATS4 and KAT8 are positively correlated and high levels of these two proteins are associated with poor overall survival in BC patients. Importantly, suppression of YEATS4 acetylation with the KAT8 inhibitor MG149 decreased YEATS4 acetylation, reduced cell viability, and sensitized BC cells to cisplatin treatment. The findings reveal a critical role of the KAT8/YEATS4 axis in both tumor growth and cisplatin sensitivity in BC cells, potentially generating a novel therapeutic strategy for BC patients.
Insights
YEATS domain-containing protein 4 (YEATS4) is crucial for bladder cancer (BC) cell survival. Inhibiting its acetylation sensitizes BC cells to cisplatin, offering a potential new therapy for bladder cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Bladder cancer (BC) presents significant challenges due to high relapse rates and limited targeted therapies.
- Identifying novel molecular targets is critical for improving BC treatment outcomes.
Purpose of the Study:
- To investigate the role of YEATS domain-containing protein 4 (YEATS4) in bladder cancer cell viability.
- To elucidate the regulatory mechanism of YEATS4 stability and its impact on BC progression.
- To explore the therapeutic potential of targeting the KAT8/YEATS4 axis in BC.
Main Methods:
- CRISPR-Cas9 library screening to identify essential genes in BC.
- Protein Stability Regulators Screening Assay to determine E3 ligase activity.
- Western blotting and immunoprecipitation to analyze protein interactions and modifications.
- Pharmacological inhibition of KAT8 using MG149.
Main Results:
- YEATS4 was identified as an essential gene for bladder cancer cell viability.
- HUWE1 was identified as the E3 ligase responsible for YEATS4 ubiquitination and degradation.
- KAT8-mediated acetylation of YEATS4 inhibits its interaction with HUWE1, preventing degradation.
- High levels of YEATS4 and KAT8 correlate with poor patient survival.
- Inhibition of YEATS4 acetylation by MG149 reduced cell viability and enhanced cisplatin sensitivity.
Conclusions:
- The KAT8/YEATS4 axis plays a critical role in bladder cancer growth and chemoresistance.
- Targeting YEATS4 acetylation presents a promising therapeutic strategy for bladder cancer.
