The Mechanism Of The Hippo Pathway Component VGLL4 In Regulating Muscle Regeneration And The Development Of Hepatocellular Carcinoma

Hippo pathway,evolutionarily conserved from Drosophila to mammals,precisely controls organ size and tissue homeostasis,which has also been implicated in promoting stem cell self-renewal and tissue repair.VGLL4,a new member of the Hippo pathway,inhibits cell proliferation by competing with YAP to bind TEADs.Skeletal muscle has regeneration ability due to the existence of adult muscle satellite cells(MuSCs).In the case of muscle injury,aging or disease,adult muscle satellite cells are activated,and undergo cell proliferation and cell differentiation to achieve self-repair and regeneration.Skeletal muscle development and regeneration are tightly regulated by muscle-specific transcriptional factors.MyoD is the master regulator of myogenesis,which directly activates the transcription of MyoG for terminal differentiation of myoblasts.The proliferation and differentiation of MuSCs are regulated through multiple signaling pathways.We identify that VGLL4 exhibits opposing effects on TEAD4-mediated transcriptional activation in YAP dependent or independent manner at different stages of muscle regeneration,thereby coordinating the balance between MuSCs proliferation and differentiation.MuSCs-specific VGLL4 knockout mice display increased MuSCs proliferation and impaired MuSCs-derived myoblasts differentiation,ultimately resulting in muscle regeneration defects.Mechanistically,at the proliferation stage of muscle regeneration,VGLL4 functions as a YAP repressor to inhibit the YAP-TEAD4 complex-mediated transcriptional activation and MuSCs proliferation.At the differentiation stage of muscle regeneration,VGLL4 acts as an indispensable co-activator of TEAD4 to regulate MyoG transcription and the YAP independent function plays critical role in facilitating the initiation of MuSCs differentiation.Moreover,VGLL4 stabilizes the interaction between MyoD and TEAD4 to achieve efficient MyoG activation.These findings define the dual roles of VGLL4 in muscle regeneration at different stages,which may open novel therapeutic perspectives for muscle regeneration.Hepatocellular carcinoma(HCC),one of the few neoplasms with high incidence and mortality.In this study,we clarify the clinical importance of IRF2BP2 in liver cancer suppression for the first time,and uncover that IRF2BP2 acts as a novel tumor suppressor in HCC.Hippo pathway precisely controls cell growth and tumorigenesis by restricting the oncogenic activity of YAP.However,therapies targeting YAP for the prevention and treatment of HCC remain limited.Our study reveals the clinical relevance and the feedback regulatory loop between the tumor suppressor IRF2BP2 and oncogene YAP in HCC.Our data show that IRF2BP2 is a novel target gene repressed by the YAP-TEAD transcriptional complex,and exhibits potent antitumor activity by inhibiting YAP activity.We also identify that IRF2BP2 interacts with the conserved motif of VGLL4 and prevents the degradation of VGLL4,which leads to synergistic inhibition toward YAP.Furthermore,liver-specific IRF2BP2 overexpression strongly suppresses liver tumor formation induced by Hippo pathway inactivation.Our findings identify a novel IRF2BP2-VGLL4-YAP feedback loop revealing the role and the molecular mechanism of how IRF2BP2 associates with Hippo pathway to regulate liver cancer progression,which may propose a potential strategy for HCC therapy and diagnosis.