Referencia

junio15Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nat. Med. in press (2015)

Autores

Miguel Vizoso, Humberto J Ferreira, Paula Lopez-Serra, F Javier Carmona, Anna Martínez-Cardús,Maria Romina Girotti, Alberto Villanueva, Sonia Guil, Catia Moutinho, Julia Liz, Anna Portela,Holger Heyn, Sebastian Moran, August Vidal, Maria Martinez-Iniesta, Jose L Manzano,Maria Teresa Fernandez-Figueras, Elena Elez, Eva Muñoz-Couselo, Rafael Botella-Estrada,Alfonso Berrocal, Fredrik Pontén, Joost van den Oord, William M Gallagher, Dennie T Frederick,Keith T Flaherty, Ultan McDermott, Paul Lorigan, Richard Marais y Manel Esteller

Resumen

Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.

Descripción

En el presente estudio se ha identificado la reactivación epigenética de una variante génica durmiente en tejidos sanos, íntimamente ligada al proceso de metastatización de los tumores de melanoma. Dicha modificación ha demostrado tener potentes implicaciones en su capacidad de predecir la evolución de los pacientes a la enfermedad y la respuesta a los actuales tratamientos que se suministran actualmente en la clínica.

fotojulio2015

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Epigenética del Cáncer del Instituto de Investigación Biomédica de Bellvitge (IDIBELL) dirigido por el Dr. Manel Esteller tiene como objetivo la investigación de las alteraciones de la metilación del DNA, las modificaciones de histonas y el RNA no codificante de proteínas (ncRNAs), para encontrar la relación de estos fenómenos con el desarrollo del cáncer en humanos. En concreto el investigador Miguel Vizoso se centra en el estudio de marcadores epigenéticos basados en la metilación del ADN que se puedan emplear para una mejor estratificación de los pacientes aquejados de melanoma metastásico así como de desenmascarar los mecanismos moleculares de resistencia generados en los pacientes a los fármacos que se les suministran para combatir la enfermedad.

Descárgate este artículo aquí.

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

Structure–Function of MamC Loop and Its Effect on the *in Vitro* Precipitation of Biomimetic Magnetite Nanoparticles

01-09-2019

MamC, an integral protein of the magnetosome membrane, has recently been proposed as a strong candidate to produce biomimetic (magnetosome-like) magnetite nanoparticles that could be used as an alternative to...

Leer más

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Leer más

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Leer más

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Leer más

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements

01-05-2019

/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Leer más

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Leer más

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Leer más

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Leer más

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

02-01-2019

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of...

Leer más

Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions

01-12-2018

Cytosolic phosphoenolpyruvate carboxykinase (PCK1) is considered a gluconeogenic enzyme; however, its metabolic functions and regulatory mechanisms beyond gluconeogenesis are poorly understood. Here, we describe that dynamic acetylation of PCK1 interconverts...

Leer más

Socios Protectores