title: MicroRNA 211 Functions as a Metabolic Switch in Human Melanoma Cells.
abstract: MicroRNA 211 (miR-211) negatively regulates genes that drive invasion of metastatic melanoma. Compared to normal human melanocytes, miR-211 expression is significantly reduced or absent in nonpigmented melanoma cells and lost during human melanoma progression. To investigate the molecular mechanism of its tumor suppressor function, miR-211 was ectopically expressed in nonpigmented melanoma cells. Ectopic expression of miR-211 reduced hypoxia-inducible factor 1α (HIF-1α) protein levels and decreased cell growth during hypoxia. HIF-1α protein loss was correlated with the downregulation of a miR-211 target gene, pyruvate dehydrogenase kinase 4 (PDK4). We present evidence that resumption of miR-211-mediated downregulation of PDK4 in melanoma cells causes inhibition of invasion by nonpigmented melanomas via HIF-1α protein destabilization. Thus, the tumor suppressor miR-211 acts as a metabolic switch, and its loss is expected to promote cancer hallmarks in human melanomas. Melanoma, one of the deadliest forms of skin cancer, kills nearly 10,000 people in the United States per year. We had previously shown that a small noncoding RNA, termed miR-211, suppresses invasion and the growth of aggressive melanoma cells. The results presented here support the hypothesis that miR-211 loss in melanoma cells causes abnormal regulation of energy metabolism, which in turn allows cancer cells to survive under low oxygen concentrations-a condition that generally kills normal cells. These findings highlight a novel mechanism of melanoma formation: miR-211 is a molecular switch that is turned off in melanoma cells, raising the hope that in the future we might be able to turn the switch back on, thus providing a better treatment option for melanoma.
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Mazar
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Qi
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Bongyong
authors.initials: B
authors.lastname: Lee
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: John
authors.initials: J
authors.lastname: Marchica
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Govindarajan
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: John
authors.initials: J
authors.lastname: Shelley
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Keck Graduate Institute, Claremont, California, USA.
authors.forename: Animesh
authors.initials: A
authors.lastname: Ray
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA rperera@sanfordburnham.org.
authors.forename: Ranjan J
authors.initials: RJ
authors.lastname: Perera
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010101:Oxygen Consumption; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: C490917:ESRRG protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C549405:MIRN211 microRNA, human; D035683:MicroRNAs; C000631432:PDK4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011960:Receptors, Estrogen; D017346:Protein Serine-Threonine Kinases