Abstract
H11/HspB8 is a functionally distinct small heat shock protein. It causes growth arrest in melanocytes, associated with the inhibition of Cyclin E/Cdk2 and β-catenin phosphorylation at the transcriptional activity site Ser(552) and is silenced through DNA methylation in 27/35 (77%) melanoma tissues/early cultures. 5-Aza-2'-deoxycytidine (Aza-C) induces melanoma cell death correlated with the levels of H11/HspB8 DNA methylation (p < .001). In line with low/moderate H11/HspB8 methylation, PI3-K inhibition increases Aza-C-induced cell death. Aza-C inhibits the growth of melanoma xenografts related to the levels of H11/HspB8 methylation, and a nonmethylated/non-TAK1 binding H11/HspB8 mutant confers Aza-C resistance. H11/HspB8 is a potential molecular marker for demethylation therapies.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / pharmacology*
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Apoptosis / drug effects
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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Cell Cycle
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DNA Methylation*
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Decitabine
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Female
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Heat-Shock Proteins / genetics*
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Heat-Shock Proteins / physiology
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Humans
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Melanocytes / physiology
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Melanoma / drug therapy
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Melanoma / genetics*
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Melanoma / pathology
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Mice
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Mice, Inbred BALB C
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Molecular Chaperones
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Phosphatidylinositol 3-Kinases / physiology
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins c-akt / physiology
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Xenograft Model Antitumor Assays
Substances
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Antimetabolites, Antineoplastic
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HSPB8 protein, human
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Heat-Shock Proteins
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Molecular Chaperones
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Decitabine
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Azacitidine