Abstract
Glycolytic reprogramming is a typical feature of many cancers; however, key regulators of glucose metabolism reengineering are poorly understood, especially in cutaneous squamous cell carcinoma (cSCC). Here, Homeobox A9 (HOXA9), a direct target of onco-miR-365, is identified to be significantly downregulated in cSCC tumors and cell lines. HOXA9 acts as a tumor suppressor and inhibits glycolysis in cSCC in vitro and in vivo by negatively regulating HIF-1α and its downstream glycolytic regulators, HK2, GLUT1 and PDK1. Mechanistic studies show that HOXA9-CRIP2 interaction at glycolytic gene promoters impeds HIF-1α binding, repressing gene expression in trans. Our results reveal a miR-365-HOXA9-HIF-1α regulatory axis that contributes to the enhanced glycolysis in cSCC development and may represent an intervention target for cSCC therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Aged
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Animals
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Case-Control Studies
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Cell Line, Tumor
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Cellular Reprogramming
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Female
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Gene Expression Regulation, Neoplastic*
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Glucose Transporter Type 1 / genetics
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Glucose Transporter Type 1 / metabolism
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Glycolysis / genetics
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Heterografts
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Hexokinase / genetics
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Hexokinase / metabolism
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Keratinocytes / metabolism
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Keratinocytes / pathology
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LIM Domain Proteins / genetics*
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LIM Domain Proteins / metabolism
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Male
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Middle Aged
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Promoter Regions, Genetic
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Signal Transduction
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Skin Neoplasms / genetics*
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
Substances
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Adaptor Proteins, Signal Transducing
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CRIP2 protein, human
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Glucose Transporter Type 1
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HIF1A protein, human
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Homeodomain Proteins
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Hypoxia-Inducible Factor 1, alpha Subunit
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LIM Domain Proteins
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MIRN365 microRNA, human
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MicroRNAs
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PDK1 protein, human
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Pdk1 protein, mouse
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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SLC2A1 protein, human
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homeobox protein HOXA9
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HK2 protein, human
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Hexokinase
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Protein Serine-Threonine Kinases