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

Vizoso, M
; 
Ferreira, H
; 
Lopez-Serra, P
; 
Carmona, F
; 
Martínez-Cardús, A
; 
Girotti, Maria Romina
; 
Villanueva, A
; 
Guil, S
; 
Moutinho, C
; 
Liz, J
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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.
Authors
Vizoso, M
Ferreira, H
Lopez-Serra, P
Carmona, F
Martínez-Cardús, A
Girotti, Maria Romina
Villanueva, A
Guil, S
Moutinho, C
Liz, J
Portela, A
Heyn, H
Moran, S
Vidal, A
Martinez-Iniesta, M
Manzano, J
Fernandez-Figueras, M
Elez, E
Muñoz-Couselo, E
Botella-Estrada, R
Berrocal, A
Pontén, F
Van Den Oord, J
Gallagher, W
Frederick, D
Flaherty, K
McDermott, U
Lorigan, Paul C
Marais, Richard
Esteller, M
Affiliation
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona,
Description
Date
2015-06-01
Publisher
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All Christie Publications
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Type
Article
Citation
Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. 2015: Nat Med
Journal Title
Journal ISSN
Volume Title
URI
http://hdl.handle.net/10541/558687
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