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

doi:10.1038/nm.3863

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

Cancer Research UK Manchester Institute

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	26030178
Journal	Nature Medicine
Volume	21
Issue number	7
DOIs	https://doi.org/10.1038/nm.3863
Publication status	Published - Jul 2015

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Vizoso, M., Ferreira, H. J., Lopez-Serra, P., Carmona, F. J., Martínez-Cardús, A., Girotti, M. R., Villanueva, A., Guil, S., Moutinho, C., Liz, J., Portela, A., Heyn, H., Moran, S., Vidal, A., Martinez-Iniesta, M., Manzano, J. L., Fernandez-Figueras, M. T., Elez, E., Muñoz-Couselo, E., ... Esteller, M. (2015). Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nature Medicine, 21(7), Article 26030178. https://doi.org/10.1038/nm.3863

@article{dc57f5b52f5d4fbab3657967206e4c6b,

title = "Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.",

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.",

author = "Miguel Vizoso and Ferreira, {Humberto J} and Paula Lopez-Serra and Carmona, {F Javier} and Anna Mart{\'i}nez-Card{\'u}s and Girotti, {Maria Romina} and Alberto Villanueva and Sonia Guil and Catia Moutinho and Julia Liz and Anna Portela and Holger Heyn and Sebastian Moran and August Vidal and Maria Martinez-Iniesta and Manzano, {Jose L} and Fernandez-Figueras, {Maria Teresa} and Elena Elez and Eva Mu{\~n}oz-Couselo and Rafael Botella-Estrada and Alfonso Berrocal and Fredrik Pont{\'e}n and Oord, {Joost van den} and Gallagher, {William M} and Frederick, {Dennie T} and Flaherty, {Keith T} and Ultan McDermott and Paul Lorigan and Richard Marais and Manel Esteller",

note = "100282/Z/12/Z, Wellcome Trust, United Kingdom",

year = "2015",

month = jul,

doi = "10.1038/nm.3863",

language = "English",

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Vizoso, M, Ferreira, HJ, Lopez-Serra, P, Carmona, FJ, Martínez-Cardús, A, Girotti, MR, Villanueva, A, Guil, S, Moutinho, C, Liz, J, Portela, A, Heyn, H, Moran, S, Vidal, A, Martinez-Iniesta, M, Manzano, JL, Fernandez-Figueras, MT, Elez, E, Muñoz-Couselo, E, Botella-Estrada, R, Berrocal, A, Pontén, F, Oord, JVD, Gallagher, WM, Frederick, DT, Flaherty, KT, McDermott, U, Lorigan, P, Marais, R & Esteller, M 2015, 'Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.', Nature Medicine, vol. 21, no. 7, 26030178. https://doi.org/10.1038/nm.3863

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T1 - Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.

AU - Vizoso, Miguel

AU - Ferreira, Humberto J

AU - Lopez-Serra, Paula

AU - Carmona, F Javier

AU - Martínez-Cardús, Anna

AU - Girotti, Maria Romina

AU - Villanueva, Alberto

AU - Guil, Sonia

AU - Moutinho, Catia

AU - Liz, Julia

AU - Portela, Anna

AU - Heyn, Holger

AU - Moran, Sebastian

AU - Vidal, August

AU - Martinez-Iniesta, Maria

AU - Manzano, Jose L

AU - Fernandez-Figueras, Maria Teresa

AU - Elez, Elena

AU - Muñoz-Couselo, Eva

AU - Botella-Estrada, Rafael

AU - Berrocal, Alfonso

AU - Pontén, Fredrik

AU - Oord, Joost van den

AU - Gallagher, William M

AU - Frederick, Dennie T

AU - Flaherty, Keith T

AU - McDermott, Ultan

AU - Lorigan, Paul

AU - Marais, Richard

AU - Esteller, Manel

N1 - 100282/Z/12/Z, Wellcome Trust, United Kingdom

PY - 2015/7

Y1 - 2015/7

N2 - 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.

AB - 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.

U2 - 10.1038/nm.3863

DO - 10.1038/nm.3863

M3 - Article

C2 - 26030178

VL - 21

JO - Nature Medicine

JF - Nature Medicine

IS - 7

M1 - 26030178

ER -

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

Abstract

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