Oxytocin Receptor Regulates the Hippo/YAP Axis to Drive Hepatocarcinogenesis

Abstract Dysregulation of Hippo signaling, especially the downstream effector YAP, is a critical driver of hepatocellular carcinoma (HCC). Therefore, identifying therapeutic targets to block Hippo signaling could help improve survival outcomes for patients with HCC. In this study, we conducted an unbiased siRNA screen on G protein–coupled receptors targeted by drugs approved in the United States and strongly associated with the Hippo/YAP pathway and identified the oxytocin receptor (OXTR) as an important activator of the Hippo/YAP axis in HCC. The OXTR was correlated with the Hippo gene signature and poor survival outcomes in HCC, and OXTR activation promoted HCC progression through the Hippo/YAP axis. The OXTR antagonist atosiban blocked the growth of HCC in xenograft, patient-derived explant, organoid, and MST1/2 double-knockout mouse models. Molecular studies revealed that activation of the OXTR facilitated YAP dephosphorylation, nuclear accumulation, and transcriptional activation in HCC. OXTR interacted with Gαq/11 at several important sites (R137, I141, and I227) and induced YAP activation through the Gαq/11/Rho-associated protein kinase/LATS axis. Chromatin immunoprecipitation assays showed that YAP bound to the enhancer region of the OXTR and facilitated its transcription, creating a positive feedback loop. Together, this study uncovered the interplay between Hippo signaling and the OXTR pathway in hepatocarcinogenesis and established OXTR inhibition with atosiban as a promising strategy for treating HCC. Significance: The FDA-approved oxytocin receptor antagonist atosiban can ameliorate Hippo signaling dysfunction in liver cancer to suppress tumor growth, providing an effective and rapidly translatable therapy for hepatocellular carcinoma.