RESUMO
Evolutionarily conserved, the Hippo signaling pathway is critical in regulating organ size and tissue homeostasis. The activity of this pathway is tightly regulated under normal circumstances, since its physical function is precisely maintained to control the rate of cell proliferation. Failure of maintenance leads to a variety of tumors. Our understanding of the mechanism of Hippo dysregulation and tumorigenesis is becoming increasingly precise, relying on the emergence of upstream inhibitor or activator and the connection linking Hippo target genes, mutations, and related signaling pathways with phenotypes. In this review, we summarize recent reports on the signaling network of the Hippo pathway in tumorigenesis and progression by exploring its critical mechanisms in cancer biology and potential targeting in cancer therapy.
Assuntos
Via de Sinalização Hippo , Neoplasias , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transativadores/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Neoplasias/genética , Neoplasias/patologia , Carcinogênese/genéticaRESUMO
BACKGROUND AND AIMS: The conserved Hippo pathway regulates organ size, tissue homeostasis, and tumorigenesis. Interferon regulatory factor 2 binding protein 2 (IRF2BP2) was originally identified as a transcriptional corepressor. However, the association between IRF2BP2 and the Hippo pathway remains largely unknown. In addition, the biological function and regulation mechanism of IRF2BP2 in liver cancer are poorly understood. APPROACH AND RESULTS: In this study, we uncovered the clinical significance of IRF2BP2 in suppressing hepatocellular carcinogenesis. We showed that IRF2BP2, a direct target repressed by the Yes-associated protein (YAP)/TEA domain transcription factor 4 (TEAD4) transcriptional complex, inhibited YAP activity through a feedback loop. IRF2BP2 stabilized vestigial-like family member 4 (VGLL4) and further enhanced VGLL4's inhibitory function on YAP. Moreover, liver-specific IRF2BP2 overexpression suppressed tumor formation induced by Hippo pathway inactivation. CONCLUSIONS: These results revealed the important role of IRF2BP2 in repressing liver cancer progression and highlighted a feedback loop underlying the Hippo pathway in organ-size control and tumorigenesis.
Assuntos
Carcinogênese/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas , Proteínas Musculares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proliferação de Células , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Via de Sinalização Hippo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Transdução de Sinais , Fatores de Transcrição de Domínio TEA , Proteínas Supressoras de Tumor/metabolismoRESUMO
The Hippo signaling pathway maintains organ size and tissue homeostasis via orchestration of cell proliferation and apoptosis. How this pathway triggers cell apoptosis remains largely unexplored. Here, we identify NR4A1 as a target of the Hippo pathway that mediates the pro-apoptotic and anti-tumor effects of the Hippo pathway whereby YAP regulates the transcription, phosphorylation, and mitochondrial localization of NR4A1. NR4A1, in turn, functions as a feedback inhibitor of YAP to promote its degradation, thereby inhibiting the function of YAP during liver regeneration and tumorigenesis. Our studies elucidate a regulatory loop between NR4A1 and YAP to coordinate Hippo signaling activity during liver regeneration and tumorigenesis and highlight NR4A1 as a marker of Hippo signaling, as well as a therapeutic target for hepatocellular carcinoma.