RESUMO
Lung cancer is the leading cause of cancer deaths. Its high mortality is associated with high metastatic potential. Here, we show that the RAC1-selective guanine nucleotide exchange factor T cell invasion and metastasis-inducing protein 1 (TIAM1) promotes cell migration and invasion in the most common subtype of lung cancer, non-small-cell lung cancer (NSCLC), through an unexpected nuclear function. We show that TIAM1 interacts with TRIM28, a master regulator of gene expression, in the nucleus of NSCLC cells. We reveal that a TIAM1-TRIM28 complex promotes epithelial-to-mesenchymal transition, a phenotypic switch implicated in cell migration and invasion. This occurs through H3K9me3-induced silencing of protocadherins and by decreasing E-cadherin expression, thereby antagonizing cell-cell adhesion. Consistently, TIAM1 or TRIM28 depletion suppresses the migration of NSCLC cells, while migration is restored by the simultaneous depletion of protocadherins. Importantly, high nuclear TIAM1 in clinical specimens is associated with advanced-stage lung adenocarcinoma, decreased patient survival, and inversely correlates with E-cadherin expression.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Protocaderinas , Carcinoma Pulmonar de Células não Pequenas/genética , Caderinas/genética , Epigênese Genética , Proteína 28 com Motivo Tripartido , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/genéticaRESUMO
The Tiam family proteins - Tiam1 and Tiam2/STEF - are Rac1-specific Guanine Nucleotide Exchange Factors (GEFs) with important functions in epithelial, neuronal, immune and other cell types. Tiam GEFs regulate cellular migration, proliferation and survival, mainly through activating and directing Rac1 signalling. Dysregulation of the Tiam GEFs is significantly associated with human diseases including cancer, immunological and neurological disorders. Uncovering the mechanisms and consequences of dysregulation is therefore imperative to improving the diagnosis and treatment of diseases. Here we compare and contrast the subcellular localisation and function of Tiam1 and Tiam2/STEF, and review the evidence for their dysregulation in disease.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neoplasias/metabolismo , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Adesão Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Humanos , Sistema Imunitário , Doenças do Sistema Nervoso/metabolismo , Neurônios/metabolismo , Domínios Proteicos , Processamento Pós-Transcricional do RNA , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Aberrant WNT signaling drives colorectal cancer (CRC). Here, we identify TIAM1 as a critical antagonist of CRC progression through inhibiting TAZ and YAP, effectors of WNT signaling. We demonstrate that TIAM1 shuttles between the cytoplasm and nucleus antagonizing TAZ/YAP by distinct mechanisms in the two compartments. In the cytoplasm, TIAM1 localizes to the destruction complex and promotes TAZ degradation by enhancing its interaction with ßTrCP. Nuclear TIAM1 suppresses TAZ/YAP interaction with TEADs, inhibiting expression of TAZ/YAP target genes implicated in epithelial-mesenchymal transition, cell migration, and invasion, and consequently suppresses CRC cell migration and invasion. Importantly, high nuclear TIAM1 in clinical specimens associates with increased CRC patient survival. Together, our findings suggest that in CRC TIAM1 suppresses tumor progression by regulating YAP/TAZ activity.