Reference

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

Authors

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

Abstract

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.

Description

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.

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