The posttranslational modifications of Hippo-YAP pathway in cancer

Background: Yes-associated protein (YAP) is a key effector of the Hippo pathway and is frequently dysregulated in aggressive human cancers. Aberrant YAP activation has emerged as an important driver of tumorigenesis, chemoresistance and metastasis. Since posttranslational modifications (PTMs) are pivotal modifiers that determine protein activation or subcellular localization, the malfunction of YAP due to dysregulated PTMs has been linked to various cancers. Collectively, although YAP has long been considered an undruggable transcription cofactor, its PTMs may be its Achilles' heel. To provide theoretical support for developing small molecule inhibitors based on PTMs, in this review article, we summarize the current understanding of the impact of PTMs in regulating the Hippo-YAP pathway and further discuss potential therapeutic intervention. Scope of review: In our review, we summarize the known posttranslational modifications (PTMs) of YAP that dictate its protein stability, transcriptional activity and subcellular localization at different stages. Here, we clearly summarize the specific enzymes and sites involved in YAP PTMs and place additional focus on the consequences of PTM-modulated YAP activity and translocation. Main conclusion: PTMs of YAP play fundamental roles in controlling the protein abundance and function. Therefore, interfering with PTMs of YAP may contribute to solving the undruggable problem in YAP inhibition, thus providing new approaches for YAP-based cancer therapy. General significance: Future studies that target corresponding PTM-related kinases/enzymes will provide new strategies for cancer therapy, particularly in tumors with YAP dysregulation.