RESUMO
Runt-related transcription factor 3 (RUNX3) is a well-documented tumour suppressor that is frequently inactivated in gastric cancer. Here, we define a novel mechanism by which RUNX3 exerts its tumour suppressor activity involving the TEAD-YAP complex, a potent positive regulator of proliferative genes. We report that the TEAD-YAP complex is not only frequently hyperactivated in liver and breast cancer, but also confers a strong oncogenic activity in gastric epithelial cells. The increased expression of TEAD-YAP in tumour tissues significantly correlates with poorer overall survival of gastric cancer patients. Strikingly, RUNX3 physically interacts with the N-terminal region of TEAD through its Runt domain. This interaction markedly reduces the DNA-binding ability of TEAD that attenuates the downstream signalling of TEAD-YAP complex. Mutation of RUNX3 at Arginine 122 to Cysteine, which was previously identified in gastric cancer, impairs the interaction between RUNX3 and TEAD. Our data reveal that RUNX3 acts as a tumour suppressor by negatively regulating the TEAD-YAP oncogenic complex in gastric carcinogenesis.
Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Neoplasias Gástricas/patologia , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Carcinogênese , Linhagem Celular Tumoral , Subunidade alfa 3 de Fator de Ligação ao Core/química , Subunidade alfa 3 de Fator de Ligação ao Core/genética , DNA/metabolismo , Células Epiteliais/metabolismo , Humanos , Mutação , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/químicaRESUMO
The study of RUNX3 in tumor pathogenesis is a rapidly expanding area of cancer research. Functional inactivation of RUNX3-through mutation, epigenetic silencing, or cytoplasmic mislocalization-is frequently observed in solid tumors of diverse origins. This alone indicates that RUNX3 inactivation is a major risk factor in tumorigenesis and that it occurs early during progression to malignancy. Conversely, RUNX3 has also been described to have an oncogenic function in a subset of tumors. Although the mechanism of how RUNX3 switches from tumor suppressive to oncogenic activity is unclear, this is of clinical relevance with implications for cancer detection and prognosis. Recent developments have significantly contributed to our understanding of the pleiotropic tumor suppressive properties of RUNX3 that regulate major signaling pathways. This review summarizes the important findings that link RUNX3 to tumor suppression.