Identifying TEAD Proteins Role and Disrupting YAP1 to Inhibit Oncogenic YAP1 Fusions

Overview

Gene fusions are chromosomal aberrations that can have oncogenic functions, causing nearly 20% of global cancer morbidity. This investigation focused on YAP1 fusions. YAP1(yes associated protein 1), a proto-oncogene driving cell growth, functions by interaction with TEAD (transcriptional enhancer factor) proteins. The aim of this project was to identify the role of the four TEAD proteins on YAP1 activity of YAP1-in brain tumors (YAP1-MAMLD1 and soft tissue sarcomas (YAP1-TFE3), and the ability of Dasatinib (a nuclear exclusion triggering drug) to inhibit YAP1 activity of the fusions. The presence of all four TEAD proteins was determined using a polymerase chain reaction. RNA interference was used to silence specific TEAD proteins, and YAP1 activity was then measured using a luciferase assay (that measures gene activity using light). For the second part of the project, after seeding cells with different concentrations of Dasatinib, another luciferase assay was used to measure YAP1 activity. The presence of all four TEAD proteins in the cell line was confirmed. TEAD 2 and 4 were expressed at significantly higher levels than TEAD 1 and 3 (padj < 0.002). Furthermore, wild type YAP1 (padj=0.0004) and YAP1-MAMLD1(padj<0.0001) showed significant reduction in YAP1 activity upon silencing of TEAD1-4 expression, while TEAD silencing had no significant effect on YAP1-TFE3. Lastly, Dasatinib treatment led to significant reduction of wild type YAP1 activity (p=0.002). These findings indicate that YAP1 activity in the fusions relies on TEAD interaction; hence the YAP1/TEAD complex is a potential therapeutic target to inhibit cancer cell proliferation.

Competition history

• AJAS 2020 Category not listed

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