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1.
Cancer Lett ; 357(1): 412-418, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25475555

RESUMEN

In neuroblastoma, MYCN amplification is associated with a worse prognosis and is a criterion used in the clinic to provide intensive treatments to children even with localized disease. In correlation with MYCN amplification, upregulation of TWIST1, a transcription factor playing a crucial role in inhibition of apoptosis and differentiation, was previously reported. Clinical data set analysis of MYCN, MYC and TWIST1 expression permits us to confirm that TWIST1 expression is upregulated in MYCN amplified neuroblastoma but also in a subset of neuroblastoma harboring high expression of MYCN or MYC without gene amplification. In silico analyses reveal the presence of several MYC regulatory motifs (E-Boxes and INR) within the TWIST1 promoter. Using gel shift assay and reporter activity assays, we demonstrate that both N-Myc and c-Myc proteins can bind and activate the TWIST1 promoter. Therefore, we propose TWIST1 as a direct MYC transcriptional target.


Asunto(s)
Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteína 1 Relacionada con Twist/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Genes myc , Humanos , Proteína Proto-Oncogénica N-Myc , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , Transfección , Proteína 1 Relacionada con Twist/metabolismo
2.
Mol Cancer Ther ; 12(6): 925-36, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23536719

RESUMEN

CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET- and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration.


Asunto(s)
Receptores ErbB/metabolismo , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/administración & dosificación , Quinazolinas/administración & dosificación , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Regulación Neoplásica de la Expresión Génica , Inhibidores de Histona Desacetilasas/administración & dosificación , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Proteínas Proto-Oncogénicas c-met/genética , Receptor ErbB-2/antagonistas & inhibidores , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología
3.
PLoS One ; 7(12): e53498, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23300933

RESUMEN

BACKGROUND: Morphogenesis results from the coordination of distinct cell signaling pathways controlling migration, differentiation, apoptosis, and proliferation, along stem/progenitor cell dynamics. To decipher this puzzle, we focused on epithelial-mesenchymal transition (EMT) "master genes". EMT has emerged as a unifying concept, involving cell-cell adhesion, migration and apoptotic pathways. EMT also appears to mingle with stemness. However, very little is known on the physiological role and relevance of EMT master-genes. We addressed this question during mammary morphogenesis. Recently, a link between Slug/Snai2 and stemness has been described in mammary epithelial cells, but EMT master genes actual localization, role and targets during mammary gland morphogenesis are not known and we focused on this basic question. METHODOLOGY/PRINCIPAL FINDINGS: Using a Slug-lacZ transgenic model and immunolocalization, we located Slug in a distinct subpopulation covering about 10-20% basal cap and duct cells, mostly cycling cells, coexpressed with basal markers P-cadherin, CK5 and CD49f. During puberty, Slug-deficient mammary epithelium exhibited a delayed development after transplantation, contained less cycling cells, and overexpressed CK8/18, ER, GATA3 and BMI1 genes, linked to luminal lineage. Other EMT master genes were overexpressed, suggesting compensation mechanisms. Gain/loss-of-function in vitro experiments confirmed Slug control of mammary epithelial cell luminal differentiation and proliferation. In addition, they showed that Slug enhances specifically clonal mammosphere emergence and growth, cell motility, and represses apoptosis. Strikingly, Slug-deprived mammary epithelial cells lost their potential to generate secondary clonal mammospheres. CONCLUSIONS/SIGNIFICANCE: We conclude that Slug pathway controls the growth dynamics of a subpopulation of cycling progenitor basal cells during mammary morphogenesis. Overall, our data better define a key mechanism coordinating cell lineage dynamics and morphogenesis, and provide physiological relevance to broadening EMT pathways.


Asunto(s)
Diferenciación Celular , Células Epiteliales/metabolismo , Glándulas Mamarias Animales/embriología , Factores de Transcripción/genética , Animales , Adhesión Celular , Movimiento Celular , Proliferación Celular , Células Epiteliales/citología , Transición Epitelial-Mesenquimal , Femenino , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/metabolismo , Ratones , Morfogénesis , Factores de Transcripción de la Familia Snail , Factores de Transcripción/metabolismo
4.
Cancer Cell ; 14(1): 79-89, 2008 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-18598946

RESUMEN

Twist1 and Twist2 are major regulators of embryogenesis. Twist1 has been shown to favor the metastatic dissemination of cancer cells through its ability to induce an epithelial-mesenchymal transition (EMT). Here, we show that a large fraction of human cancers overexpress Twist1 and/or Twist2. Both proteins override oncogene-induced premature senescence by abrogating key regulators of the p53- and Rb-dependent pathways. Twist1 and Twist2 cooperate with Ras to transform mouse embryonic fibroblasts. Interestingly, in epithelial cells, the oncogenic cooperation between Twist proteins and activated mitogenic oncoproteins, such as Ras or ErbB2, leads to complete EMT. These findings suggest an unanticipated direct link between early escape from failsafe programs and the acquisition of invasive features by cancer cells.


Asunto(s)
Transdiferenciación Celular , Transformación Celular Neoplásica/metabolismo , Senescencia Celular , Células Epiteliales/metabolismo , Fibroblastos/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Animales , Línea Celular , Transdiferenciación Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Senescencia Celular/genética , Perros , Activación Enzimática , Células Epiteliales/enzimología , Células Epiteliales/patología , Fibroblastos/enzimología , Fibroblastos/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Glándulas Mamarias Humanas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Desnudos , Ratones Transgénicos , Invasividad Neoplásica , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Proteínas Nucleares/genética , Interferencia de ARN , Proteínas Represoras/genética , Proteína de Retinoblastoma/metabolismo , Transfección , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/metabolismo , Proteína 1 Relacionada con Twist/genética , Regulación hacia Arriba , Proteínas ras/metabolismo
5.
Genetics ; 173(2): 579-87, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16582449

RESUMEN

Eukaryotic genomes contain euchromatic regions, which are transcriptionally active, and heterochromatic regions, which are repressed. These domains are separated by "barrier elements": DNA sequences that protect euchromatic regions from encroachment by neighboring heterochromatin. To identify proteins that play a role in the function of barrier elements we have carried out a screen in S. cerevisiae. We recovered the gene HHO1, which encodes the yeast ortholog of histone H1, as a high-copy modifier of barrier activity. Histone H1 is a linker histone that binds the outside of nucleosomes and modifies chromatin dynamics. Here we show that Hho1p reinforces the action of several types of barrier elements, and also inhibits silencing on its own.


Asunto(s)
Silenciador del Gen , Genes Fúngicos , Histonas/genética , Histonas/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Secuencia de Aminoácidos , Datos de Secuencia Molecular , Nucleosomas/genética , Nucleosomas/metabolismo , Unión Proteica , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/genética , Proteínas Reguladoras de Información Silente de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética
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