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

Nat Med. 2015 Jul;21(7):741-50. doi: 10.1038/nm.3863. Epub 2015 Jun 1.

Authors

Miguel Vizoso¹, Humberto J Ferreira¹, Paula Lopez-Serra¹, F Javier Carmona¹, Anna Martínez-Cardús¹, Maria Romina Girotti², Alberto Villanueva³, Sonia Guil¹, Catia Moutinho¹, Julia Liz¹, Anna Portela¹, Holger Heyn¹, Sebastian Moran¹, August Vidal⁴, Maria Martinez-Iniesta³, Jose L Manzano⁵, Maria Teresa Fernandez-Figueras⁶, Elena Elez⁷, Eva Muñoz-Couselo⁷, Rafael Botella-Estrada⁸, Alfonso Berrocal⁹, Fredrik Pontén¹⁰, Joost van den Oord¹¹, William M Gallagher¹², Dennie T Frederick¹³, Keith T Flaherty¹³, Ultan McDermott¹⁴, Paul Lorigan¹⁵, Richard Marais², Manel Esteller¹⁶

Affiliations

¹ Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
² Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, UK.
³ Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
⁴ Department of Pathological Anatomy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
⁵ Medical Oncology Service, Catalan Institute of Oncology, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain.
⁶ Pathology Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain.
⁷ Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain.
⁸ Dermatology Service, Hospital La Fe, Universidad de Valencia, Valencia, Spain.
⁹ Medical Oncology Service, Hospital General, Valencia, Spain.
¹⁰ Department of Pathology, University Hospital of Uppsala, Uppsala, Sweden.
¹¹ Translational Cell &Tissue Pathology, Katholieke Universiteit Leuven, Leuven, Belgium.
¹² University College Dublin School of Biomolecular and Biomedical Science, University College Dublin Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
¹³ Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
¹⁴ Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
¹⁵ University of Manchester, Christie National Health Service Foundation Trust, Manchester, UK.
¹⁶ 1] Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain. [2] Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain. [3] Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.

PMID: 26030178
PMCID: PMC4968631
DOI: 10.1038/nm.3863

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
DNA Methylation / drug effects
DNA Methylation / genetics
Disease Progression*
Epigenesis, Genetic* / drug effects
ErbB Receptors / metabolism*
GTPase-Activating Proteins / genetics*
GTPase-Activating Proteins / metabolism
Immunoprecipitation
Melanoma / genetics*
Melanoma / pathology*
Mice, Nude
Molecular Weight
Neoplasm Metastasis
Prognosis
Promoter Regions, Genetic / genetics
Protein Binding / drug effects
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Kinase Inhibitors / pharmacology
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Signal Transduction / drug effects
Transcriptional Activation / drug effects
Transcriptional Activation / genetics
Treatment Outcome
rab GTP-Binding Proteins / metabolism

Substances

GTPase-Activating Proteins
Protein Isoforms
Protein Kinase Inhibitors
RNA, Messenger
RNA, Small Interfering
TBC1D16 protein, human
ErbB Receptors
rab GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding