Journal
ONCOTARGET
Volume 8, Issue 20, Pages 32946-32959Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.16514
Keywords
melanoma; glucose; MITF; ATF4; ROS
Categories
Funding
- Cancer Research UK [C11591/A16416]
- Miguel Servet contract [CP15/00176]
- Fondo de Investigacion Sanitario (FIS) from the Instituto de Salud Carlos III-FEDER (Fondo Europeo de Desarrollo Regional) [PI16-01911]
- MRC [MR/L011840/1] Funding Source: UKRI
- Cancer Research UK [16416] Funding Source: researchfish
- Medical Research Council [MR/L011840/1] Funding Source: researchfish
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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.
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