RESUMO
Tumor suppressor gene silencing through cytosine methylation contributes to cancer formation. Whether DNA demethylation enzymes counteract this oncogenic effect is unknown. Here, we show that TET1, a dioxygenase involved in cytosine demethylation, is downregulated in prostate and breast cancer tissues. TET1 depletion facilitates cell invasion, tumor growth, and cancer metastasis in prostate xenograft models and correlates with poor survival rates in breast cancer patients. Consistently, enforced expression of TET1 reduces cell invasion and breast xenograft tumor formation. Mechanistically, TET1 suppresses cell invasion through its dioxygenase and DNA binding activities. Furthermore, TET1 maintains the expression of tissue inhibitors of metalloproteinase (TIMP) family proteins 2 and 3 by inhibiting their DNA methylation. Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. Together, these results illustrate a mechanism by which TET1 suppresses tumor development and invasion partly through downregulation of critical gene methylation.
Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Inibidor Tecidual de Metaloproteinase-2/biossíntese , Inibidor Tecidual de Metaloproteinase-3/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Metilação de DNA/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Dioxigenases/metabolismo , Regulação para Baixo/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oxigenases de Função Mista , Invasividade Neoplásica , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Breast cancer amplified sequence 2 (BCAS2) was reported previously as a transcriptional coactivator of estrogen receptor. Here, we report that BCAS2 directly interacts with p53 to reduce p53 transcriptional activity by mildly but consistently decreasing p53 protein in the absence of DNA damage. However, in the presence of DNA damage, BCAS2 prominently reduces p53 protein and provides protection against chemotherapeutic agent such as doxorubicin. Deprivation of BCAS2 induces apoptosis in p53 wild-type cells but causes G(2)-M arrest in p53-null or p53 mutant cells. There are at least two apoptosis mechanisms induced by silencing BCAS2 in wild-type p53-containing cells. Firstly, it increases p53 retention in nucleus that triggers the expression of apoptosis-related genes. Secondly, it increases p53 transcriptional activity by raising p53 phosphorylation at Ser(46) and decreases p53 protein degradation by reducing p53 phosphorylation at Ser(315). We show for the first time that BCAS2, a small nuclear protein (26 kDa), is a novel negative regulator of p53 and hence a potential molecular target for cancer therapy.