Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR

Metastasis is respoMetastasis 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 methylatio...

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Detalhes bibliográficos
Autores: Vizoso, Miguel, Ferreira, Humberto J., López Serra, Paula, Carmona, F. Javier, Martínez Cardús, Anna, Girotti, Maria Romina, Villanueva Garatachea, Alberto, Guil, Sonia, Moutinho, Cátia, Liz, Julia, Portela, Anna, Heyn, Holger, Moran, Sebastian, Vidal-Bel, August, Martínez Iniesta, María, Manzano, José Luis, Fernandez-Figueras, Maria Teresa, Élez, Elena, Muñoz-Couselo, Eva, Botella Estrada, Rafael, Berrocal, Alfonso, Pontén, Fredrik, Oord, Joost van den, Gallagher, William M., DenFrederick, Dennie T., Flaherty, Keith T., McDermott, Ultan, Lorigan, Paul, Marais, Richard, Esteller, Manel, 1968-
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2015
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/110925
Acesso em linha:https://hdl.handle.net/2445/110925
Access Level:acceso abierto
Palavra-chave:Melanoma
Metàstasi
Epigènesi
Metilació
Proteïnes supressores de tumors
Metastasis
Epigenesis
Methylation
Tumor suppressor protein
Descrição
Resumo:Metastasis is respoMetastasis 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.

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