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.
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Vizoso
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Humberto J
authors.initials: HJ
authors.lastname: Ferreira
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Lopez-Serra
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Carmona
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Martínez-Cardús
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, UK.
authors.forename: Maria Romina
authors.initials: MR
authors.lastname: Girotti
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Guil
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Catia
authors.initials: C
authors.lastname: Moutinho
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Liz
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Portela
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: Department of Pathological Anatomy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: August
authors.identifier: 0000000157272099
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Iniesta
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Manzano
authors.affiliation: Pathology Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain.
authors.forename: Maria Teresa
authors.identifier: 0000000223667110
authors.initials: MT
authors.lastname: Fernandez-Figueras
authors.affiliation: Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Elez
authors.affiliation: Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Muñoz-Couselo
authors.affiliation: Dermatology Service, Hospital La Fe, Universidad de Valencia, Valencia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Botella-Estrada
authors.affiliation: Medical Oncology Service, Hospital General, Valencia, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Berrocal
authors.affiliation: Department of Pathology, University Hospital of Uppsala, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Translational Cell &Tissue Pathology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Joost van den
authors.initials: Jv
authors.lastname: Oord
authors.affiliation: University College Dublin School of Biomolecular and Biomedical Science, University College Dublin Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: William M
authors.initials: WM
authors.lastname: Gallagher
authors.affiliation: Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: University of Manchester, Christie National Health Service Foundation Trust, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.affiliation: 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.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D047468:Immunoprecipitation; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008819:Mice, Nude; D008970:Molecular Weight; D009362:Neoplasm Metastasis; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D016896:Treatment Outcome; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C555060:TBC1D16 protein, human; D066246:ErbB Receptors; D020691:rab GTP-Binding Proteins