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RESEARCH PRODUCT
Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR
Fredrik PonténRafael Botella-estradaMiguel VizosoUltan McdermottJose Luis ManzanoAnna Martínez-cardúsCatia MoutinhoJoost Van Den OordMaría Martínez-iniestaAlberto VillanuevaPaula Lopez-serraAugust VidalSebastian MoranElena ElezF. Javier CarmonaJulia LizMaria Romina GirottiHolger HeynSonia GuilAlfonso BerrocalPaul LoriganDennie T. FrederickMaría Teresa Fernández-figuerasHumberto J. FerreiraAnna PortelaWilliam M. GallagherRichard MaraisEva Muñoz-couseloKeith T. FlahertyManel Estellersubject
Transcriptional ActivationGTPase-activating proteinImmunoprecipitationMice NudeEditorials: Cell Cycle FeaturesBiologyBioinformaticsMethylationGeneral Biochemistry Genetics and Molecular BiologyEpigenesis GeneticMetastasisMetastasisEpigènesiMetàstasiCell Line TumormedicineAnimalsImmunoprecipitationProtein IsoformsRNA MessengerEpigeneticsNeoplasm MetastasisRNA Small InterferingPromoter Regions GeneticProteïnes supressores de tumorsProtein Kinase InhibitorsMelanomaMelanomaGTPase-Activating ProteinsGeneral MedicineMethylationDNA MethylationPrognosismedicine.diseaseTumor suppressor proteinErbB ReceptorsMolecular WeightTreatment Outcomerab GTP-Binding ProteinsDNA methylationDisease ProgressionCancer researchRabMetilacióProtein BindingSignal TransductionEpigenesisdescription
Metastasis is respoMetastasis 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-06-01 | Nature Medicine |