title: Glucose availability controls ATF4-mediated MITF suppression to drive melanoma cell growth.
abstract: It is well know that cancer cells have adopted an altered metabolism and that glucose is a major source of energy for these cells. In melanoma, enhanced glucose usage is favoured through the hyper-activated MAPK pathway, which suppresses OXPHOS and stimulates glycolysis. However, it has not been addressed how glucose availability impacts on melanoma specific signaling pathways that drive melanoma cell proliferation. Here we show that melanoma cells are dependent on high glucose levels for efficient growth. Thereby, glucose metabolism controls the expression of the melanoma fate transcription factor MITF, a master regulator of melanoma cell survival and proliferation, invasion and therapy resistance. Restriction of glucose availability to physiological concentrations induces the production of reactive oxygen species (ROS). Increased ROS levels lead to the up-regulation of AFT4, which in turn suppresses MITF expression by competing with CREB, an otherwise potent inducer of the MITF promoter. Our data give new insight into the complex regulation of MITF, a key regulator of melanoma biology, and support previous findings that link metabolic disorders such as hyperglycemia and diabetes with increased melanoma risk.
authors.affiliation: Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, M13 9PT, Manchester, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferguson
authors.affiliation: Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, M13 9PT, Manchester, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Smith
authors.affiliation: Navarrabiomed-Fundación Miguel Servet-Idisna, Complejo Hospitalario de Navarra, 31008, Pamplona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zudaire
authors.affiliation: Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, M13 9PT, Manchester, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wellbrock
authors.affiliation: Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, M13 9PT, Manchester, UK.|Navarrabiomed-Fundación Miguel Servet-Idisna, Complejo Hospitalario de Navarra, 31008, Pamplona, Spain.
authors.forename: Imanol
authors.initials: I
authors.lastname: Arozarena
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C497109:ATF4 protein, human; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D017382:Reactive Oxygen Species; D051701:Activating Transcription Factor 4; D005947:Glucose
keywords: ATF4; MITF; ROS; glucose; melanoma