Abstract
Expression of SHP-1 phosphatase, a key negative regulator of cell signaling, is lost in T cell lymphomas and other malignancies due to DNA methylation of the SHP-1 promoter by a currently undefined mechanism. We demonstrate that malignant T cells express DNA methyltransferase (DNMT) 1 and that constantly activated signal transducer and activator of transcription (STAT) 3 is capable of binding in vitro to DNA oligonucleotides corresponding to four STAT3 SIE/GAS binding sites identified in the SHP-1 promoter. STAT3, DNMT1, and histone deacetylase 1 form complexes and bind to the SHP-1 promoter in vivo. Treatment with pharmacologic grade DNMT1 anti-sense oligonucleotides and STAT3 small-interfering RNA induces in the malignant T cells DNA demethylation and expression of SHP-1 gene. These data indicate that STAT3 may, in part, transform cells by inducing epigenetic silencing of SHP-1 in cooperation with DNMT1 and, apparently, histone deacetylase 1. Reversal of such gene silencing represents an attractive aim for novel anticancer therapies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Base Sequence
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Blotting, Western
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Cell Line, Tumor
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Chromatin Immunoprecipitation
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CpG Islands
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / metabolism*
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DNA Methylation
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DNA Modification Methylases / metabolism
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DNA-Binding Proteins / metabolism*
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Down-Regulation
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Gene Silencing*
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Histone Deacetylase 1
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Histone Deacetylases / metabolism
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Humans
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Immunohistochemistry
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins
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Lymphoma, T-Cell / metabolism
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Models, Genetic
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Molecular Sequence Data
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Promoter Regions, Genetic
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Protein Binding
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / metabolism*
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology
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Trans-Activators / metabolism*
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Transfection
Substances
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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RNA, Messenger
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RNA, Small Interfering
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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DNA Modification Methylases
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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DNMT1 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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HDAC1 protein, human
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Histone Deacetylase 1
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Histone Deacetylases