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

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-EstradaAlfonso Berrocal, Fredrik Pontén, Joost van den Oord, William M Gallagher, Dennie T Frederick, Keith T Flaherty, Ultan McDermott, Paul Lorigan, Richard Marais, Manel Esteller

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Article number26030178
JournalNature Medicine
Issue number7
Publication statusPublished - Jul 2015


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