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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
Published on: September 13, 2018
TWF2 Drives Tumor Progression and Sunitinib Resistance in Renal Cell Carcinoma through Hippo Signaling Suppression
Liangmin Fu1,2,3, Wuyuan Liao1,4, Youyan Tan2
1Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 518880, China.
Abstract:
Renal cell carcinoma (RCC) remains a formidable clinical challenge, characterized by a high propensity for metastasis and the frequent emergence of intrinsic or acquired resistance to targeted therapies. However, the molecular mechanisms underlying sunitinib resistance and tumor progression in RCC are not fully understood. This study aims to identify Twinfilin actin-binding protein (TWF2) as a key mediator of tumor aggressiveness and therapeutic resistance. TWF2 expression is markedly upregulated in RCC cells, particularly in sunitinib-resistant subtypes, and significantly associated with poor prognosis and therapeutic nonresponsiveness. Functional analyses demonstrate that TWF2 promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling. Mechanistically, TWF2 interacts with Yes-associated protein (YAP) via the binding residues: TWF2 M99 and YAP M225. By competitively displacing large tumor suppressor kinase 1, TWF2 prevents YAP ubiquitination and degradation, leading to its stabilization and subsequent nuclear translocation. Mutation of the M99 residue abolishes the tumor-promoting activity of TWF2. Furthermore, salvianolic acid E is identified as a small-molecule inhibitor of the TWF2-YAP interaction, and synergistically enhances sunitinib efficacy in RCC cell lines and patient-derived xenograft models. These findings highlight TWF2 as a promising therapeutic target for overcoming drug resistance in RCC.
Insights
Twinfilin actin-binding protein (TWF2) drives aggressive renal cell carcinoma (RCC) and sunitinib resistance by inhibiting the Hippo pathway. Targeting TWF2 offers a new strategy to overcome drug resistance in RCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Renal cell carcinoma (RCC) presents significant challenges due to metastasis and resistance to targeted therapies like sunitinib.
- The precise molecular mechanisms driving sunitinib resistance and tumor progression in RCC require further elucidation.
Purpose of the Study:
- To identify Twinfilin actin-binding protein (TWF2) as a key mediator of tumor aggressiveness and therapeutic resistance in RCC.
- To investigate the role of TWF2 in promoting RCC cell invasion, migration, metastasis, and sunitinib resistance.
Main Methods:
- Assessed TWF2 expression in RCC cell lines and patient samples, correlating it with prognosis and therapeutic response.
- Performed functional analyses to determine TWF2's impact on RCC cell behavior and Hippo signaling.
- Investigated the molecular interaction between TWF2 and Yes-associated protein (YAP) and its downstream effects.
- Identified and evaluated salvianolic acid E as a potential inhibitor of the TWF2-YAP interaction.
Main Results:
- TWF2 expression is significantly upregulated in RCC, especially in sunitinib-resistant subtypes, and linked to poor outcomes.
- TWF2 promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling pathway.
- TWF2 interacts with YAP, preventing its ubiquitination and degradation, leading to YAP stabilization and nuclear translocation.
- Salvianolic acid E inhibits the TWF2-YAP interaction and synergistically enhances sunitinib efficacy in RCC models.
Conclusions:
- TWF2 is a critical driver of RCC aggressiveness and therapeutic resistance.
- TWF2-mediated inhibition of the Hippo pathway and YAP stabilization are key mechanisms of its oncogenic activity.
- TWF2 represents a promising therapeutic target for overcoming sunitinib resistance in renal cell carcinoma.
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