Deregulation of Hippo?YAP signaling is implicated in diverse human cancers. TEAD transcription factors bind to the transcription co-activators YAP/TAZ, and control the transcriptional output of the Hippo pathway. However, it remains difficult to directly target TEAD?YAP by small molecules. We previously discovered that TEADs possess intrinsic ?enzyme-like? activities and undergo autopalmitoylation (16-carbon fatty acylation). Palmitoylation is critical for TEAD protein stability and transcriptional activation. We recently discovered that ABHD1 is a novel depalmitoylase regulating TEADs. Loss of ABHD1 in cancers might lead to sustained TEAD palmitoylation and activation of TEAD?YAP. In addition, we identified MGH-CP1 as novel chemical inhibitor of TEAD palmitoylation, providing a pharmacological tool to suppress TEAD?YAP activates in cancers.
Our specific aims of this proposal include: (1) to investigate the role of ABHD1 in regulation of TEAD depalmitoylation; (2) To optimize MGH-CP1 and develop potent and selective TEAD inhibitors. (3) To target TEAD?YAP transcriptional complex in vitro and in vivo using pharmacological tools.
TEA domain transcription factors (TEADs) are autopalmitoylated proteins, and palmitoylation is critical for its binding to co-activator YAP, and transcriptional activities. We discovered that ABHD1 is a novel depalmitoylase regulating dynamic TEAD palmitoylation, and small molecule inhibitor of TEAD palmitoylation can block YAP- dependent tumorigenesis. Understanding this novel signaling mechanism and further optimize TEAD inhibitors will provide new therapeutic strategies to target cancers with deregulated Hippo pathway.