title: Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas.
abstract: Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of the RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations.
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673; vinayt@imcb.a-star.edu.sg liyh@imcb.a-star.edu.sg.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673.
authors.forename: Hui Shan
authors.initials: HS
authors.lastname: Cheng
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.|Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore 117597.
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673; vinayt@imcb.a-star.edu.sg liyh@imcb.a-star.edu.sg.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.|Centre for Cancer Biology, University of South Australia, Adelaide, SA 5000, Australia.|Inflammation and Human Ailments Laboratory, SA Pathology, Adelaide, SA 5000, Australia.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
mesh_terms: D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010091:Oximes / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D012319:RNA Polymerase II / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D012319:RNA Polymerase II; C509186:TERT protein, human; D019098:Telomerase; D018631:ras Proteins; C561627:dabrafenib
keywords: BRAF mutations; ERK-MAPK pathway; TERT promoter mutations; cancer; telomerase reactivation