STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes.
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.
Mesh Terms:
Base Sequence, Blotting, Western, Cell Line, Tumor, Chromatin Immunoprecipitation, CpG Islands, DNA (Cytosine-5-)-Methyltransferase, DNA Methylation, DNA Modification Methylases, DNA-Binding Proteins, Down-Regulation, Gene Silencing, Histone Deacetylase 1, Histone Deacetylases, Humans, Immunohistochemistry, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Lymphoma, T-Cell, Models, Genetic, Molecular Sequence Data, Promoter Regions, Genetic, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, T-Lymphocytes, Trans-Activators, Transfection
Base Sequence, Blotting, Western, Cell Line, Tumor, Chromatin Immunoprecipitation, CpG Islands, DNA (Cytosine-5-)-Methyltransferase, DNA Methylation, DNA Modification Methylases, DNA-Binding Proteins, Down-Regulation, Gene Silencing, Histone Deacetylase 1, Histone Deacetylases, Humans, Immunohistochemistry, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Lymphoma, T-Cell, Models, Genetic, Molecular Sequence Data, Promoter Regions, Genetic, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, T-Lymphocytes, Trans-Activators, Transfection
Proc. Natl. Acad. Sci. U.S.A.
Date: May. 10, 2005
PubMed ID: 15870198
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