RESUMO
Approximately 30% of human lung cancers acquire mutations in either Keap1 or Nfe2l2, resulting in the stabilization of Nrf2, the Nfe2l2 gene product, which controls oxidative homeostasis. Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. In mouse models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a Bach1-dependent manner. Pharmacological inhibition of Ho1 suppresses metastasis in a Fbxo22-dependent manner. Human metastatic lung cancer display high levels of Ho1 and Bach1. Bach1 transcriptional signature is associated with poor survival and metastasis in lung cancer patients. We propose that Nrf2 activates a metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias Pulmonares/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/antagonistas & inibidores , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linhagem Celular Tumoral , Movimento Celular , Proteínas F-Box/antagonistas & inibidores , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Feminino , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Estimativa de Kaplan-Meier , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Metástase Neoplásica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Ativação TranscricionalRESUMO
The progression of non-alcoholic fatty liver disease (NAFLD) and the development of hepatic fibrosis is caused by changes in redox balance, leading to an increase of reactive oxygen species (ROS) levels. NAFLD patients are at risk of progressing to non-alcoholic steatohepatitis (NASH), associated to cardiovascular diseases (CVD), coronary heart disease and stroke. Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. The present work was directed to determine whether use of an inhibitor of HO-1 activity affects lipid metabolism and fibrosis process in hepatic cells. Oil Red assay and mRNA analysis were used to evaluate the triglycerides content and the lipid metabolism pathway in HepG2 cells. ROS measurement, RT-PCR and Soluble collagen assay were used to assess the intracellular oxidant, the fibrosis pathway and the soluble collagen in LX2 cells. The activity of HO-1 was inhibited using Tin Mesoporphyrin IX (SnMP). Our study demonstrates that a non-functional HO system results in an increased lipid storage and collagen release in hepatocytes. Consequently, an increase of HO-1 levels may provide a therapeutic approach to address the metabolic alterations associated with NAFLD and its progression to NASH.