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Published on: March 27, 2020
The YAP1 and EPHA3 receptor tyrosine kinase axis regulates cellular plasticity and treatment response
Marwah M Al-Mathkour1, Abdulrahman M Dwead2, Kezhan Kazaw3
1Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA, United States of America; Miller School of Medicine, University of Miami, Miami, FL, United States of America.
Abstract:
The transcriptional coregulator YAP1 and the receptor tyrosine kinase EPHA3 regulate key cellular processes, including cell interactions, motility, survival, tissue development, carcinogenesis, and metastasis. Although their individual roles have been extensively studied, their cooperative functions remain poorly understood. Here, we investigated the relationship between EPHA3 and YAP1 in human prostate tumor tissues and cell models. Integrated transcriptomic and immunological analyses reveal a strong positive correlation between YAP1 and EPHA3 expression, which is significantly associated with tumor progression. EPHA3 knockout reduces cell proliferation and increases sensitivity to the androgen receptor inhibitor enzalutamide and the YAP1-TEAD inhibitor CA3 in vitro. EPHA3 depletion also reduces GTP-bound active RHOA and phosphorylated ERK levels and differentially affects epithelial-mesenchymal transition and cancer stem cell programs. In addition, EPHA3 silencing attenuates cell migration and invasion, an effect dependent on YAP1 activation. Bioinformatics analysis further indicates that high YAP1 and EPHA3 correlate with developmental and EMT-related gene signatures. These results demonstrate that the YAP1-EPHA3 axis is a key mediator of cell survival, plasticity, and tumor progression, and may serve as a promising cancer drug target.
Insights
The study reveals a link between EPHA3 and YAP1 in prostate tumors, showing their combined role in cancer progression. Targeting this YAP1-EPHA3 axis may offer new therapeutic strategies for cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The transcriptional coregulator YAP1 and receptor tyrosine kinase EPHA3 are vital in cellular processes like development and cancer.
- While their individual functions are known, their combined roles in cancer progression are not well understood.
Purpose of the Study:
- To investigate the cooperative functions of EPHA3 and YAP1 in human prostate tumor tissues and cell models.
- To explore the YAP1-EPHA3 axis as a potential therapeutic target in prostate cancer.
Main Methods:
- Integrated transcriptomic and immunological analyses of human prostate tumor tissues.
- In vitro studies using EPHA3 knockout and depletion in cell models.
- Bioinformatics analysis of gene expression signatures.
Main Results:
- A significant positive correlation was found between YAP1 and EPHA3 expression, associated with tumor progression.
- EPHA3 knockout reduced proliferation and increased sensitivity to enzalutamide and CA3.
- EPHA3 depletion affected RHOA, ERK, EMT, and cancer stem cell programs, reducing migration and invasion.
Conclusions:
- The YAP1-EPHA3 axis is a key mediator of cell survival, plasticity, and tumor progression in prostate cancer.
- This axis represents a promising therapeutic target for novel cancer drugs.
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