Identification And Functional Study Of New Targets And Regulators In The Hippo Signaling Pathway

The Hippo signaling pathway plays indispensable role in maintaining organ size and inhibiting tumorigenesis,so identifying new regulations and regulators of Hippo signaling is particularly important in this field.The Hippo signaling pathway orchestrates of cell proliferation and apoptosis to maintain organ size and tissue homeostasis.It remains largely unexplored how this pathway induces cell apoptosis.Besides,upstream kinase complex controls the activity of downstream effectors YAP/TEAD,but the mechanism of how YAP/TEAD regulate target gene expression and the new function related to this regulation still need to be further studied.Here,we identified NR4A1 as a new target of the Hippo pathway that mediates the pro-apoptotic function and anti-tumor effect of the Hippo pathway.Hyperactivation of YAP,on the one hand,recruits NuRD complex restricting the transcriptional level of NR4A1,on the other hand,promotes the expression of phosphorylated NR4A1,which inhibits the pro-apoptotic activity of NR4A1,promotes cell proliferation,and suppresses cell apoptosis.Abnormal activation of Hippo kinases or YAP-deficiency leads to release of YAP to NR4A1 restriction,and increased NR4A1,in turn,functions as a feedback inhibitor of YAP by promoting its degradation,thereby inhibiting the oncogenic function of YAP,inhibiting cell proliferation,and promoting cell apoptosis.The negative feedback between YAP and NR4A1 ensures the cell keeping balance between cell proliferation and apoptosis and maintains normal organ size and tissue homeostasis.Loss of NR4A1 exhibits resistance to the Hippotriggered pro-apoptotic and anti-tumor functions.Our studies elucidate a NR4A1mediated Hippo signaling in apoptosis response,underline the importance of regulating NR4A1 transcription and phosphorylation in tumorigenesis,and identify NR4A1 as a new marker representing the activity of Hippo signaling.The Hippo pathway plays critical role in cell proliferation and tumorigenesis.The activity of transcription factor TEAD4 determines the final output of the whole Hippo signaling.However,the regulators and related function of TEAD4 have not been explored extensively.Here,we identified glucocorticoids(GCs)as new activators of TEAD4.GCs treatment facilitates TEAD4 nuclear accumulation and transcriptional activation in a glucocorticoid receptor(GR)-dependent manner.Mechanistically,GCs promotes the interaction between GR and TEAD4,and the complex is recruited to the TEAD4 promoter region boosting its own expression.The regulation of GCs to TEAD4 drives the breast cancer cell survival,metastasis and chemo-resistance.Clinically,the expression of TEAD4 positively correlates with GR in patients with breast cancer,and high expression of TEAD4 predicts poor survival of patients.Targeting TEAD4 pharmacologically inhibits GCs-induced breast cancer progression.Taken together,our study reveals novel regulators and role of TEAD4 in breast cancer,which will propose a new strategy for breast cancer therapy.