Abstract A43: Identification of novel YAP/TAZ regulators in metastatic cancer

Abstract

Abstract Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the downstream effectors of the Hippo tumor inhibition pathway. Studies from us and others show that inappropriate activation of YAP and/or TAZ promotes tumor growth and metastasis. Increased YAP and/or TAZ expression and nuclear localization is observed in many human cancers and often predict poor prognosis. Mutations in Hippo-YAP/TAZ pathway exist but are not common enough to explain the frequently observed increase of YAP/TAZ expression and activity in cancer. Therefore, we hypothesize that other cancer-associated pathways cause aberrant YAP/TAZ activation in cancer cells, and identifying such pathways would provide targets for treatment of YAP/TAZ-driven cancers. Furthermore, transcriptional cofactors are often difficult to target and YAP/TAZ have important functions in adult tissues. Therefore, targeting YAP/TAZ regulators may provide a nonsystemic path of targeting YAP/TAZ that could avoid severe adverse effects. To identify novel YAP/TAZ regulators in metastatic cancer cells, we screened a lentiviral shRNA library that targets 124 cancer-associated genes in A375 MA2 (MA2) cells using a YAP/TAZ-TEAD (TEA domain family members) transcriptional reporter assay. We found that 62 genes are able to regulate YAP/TAZ activity in MA2, 24 of which are already established YAP/TAZ regulators, which supports the effectiveness of our approach. The other 38 genes have not been reported previously, which are potential novel YAP/TAZ regulators. We subsequently validated these candidate YAP/TAZ regulators by examining the expression of the YAP/TAZ target gene CTGF by qPCR and phosphorylation of YAP and TAZ by Western blot in MA2 and other metastatic cell lines. We are currently pursuing several of these novel YAP/TAZ regulators to determine the mechanism through which they regulate YAP/TAZ activity and test their role in metastasis. Our results suggest that YAP/TAZ regulators are cell type and context specific and may also functionally compensate for each other. Therefore, it is critical to identify a “core” group of YAP/TAZ regulators that are important in multiple cancer types. This could provide new strategies to more effectively inhibit YAP/TAZ activation and treat metastatic cancer. Citation Format: Yuxuan Xiao, Emily Norton, Janine Warren, John Lamar. Identification of novel YAP/TAZ regulators in metastatic cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A43.