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

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

Author information

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.

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.

PMID:
26030178
PMCID:
PMC4968631
DOI:
10.1038/nm.3863
[Indexed for MEDLINE]
Free PMC Article

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