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 oligonucteotides 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.
Original language | English |
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Pages (from-to) | 6948-6953 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 102 |
Issue number | 19 |
DOIs | |
State | Published - May 10 2005 |
Keywords
- Base Sequence
- Blotting, Western
- Cell Line, Tumor
- Chromatin Immunoprecipitation
- CpG Islands
- DNA (Cytosine-5-)-Methyltransferase 1
- DNA (Cytosine-5-)-Methyltransferases/metabolism
- DNA Methylation
- DNA Modification Methylases/metabolism
- DNA-Binding Proteins/metabolism
- Down-Regulation
- Gene Silencing
- Histone Deacetylase 1
- Histone Deacetylases/metabolism
- Humans
- Immunohistochemistry
- Immunoprecipitation
- Intracellular Signaling Peptides and Proteins
- Lymphoma, T-Cell/metabolism
- Models, Genetic
- Molecular Sequence Data
- Promoter Regions, Genetic
- Protein Binding
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
- Protein Tyrosine Phosphatases/metabolism
- RNA, Messenger/metabolism
- RNA, Small Interfering/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- STAT3 Transcription Factor
- T-Lymphocytes/enzymology
- Trans-Activators/metabolism
- Transfection