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
- Research Support, N.I.H., Extramural
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- 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*
- T-Lymphocytes / immunology
- Trans-Activators / metabolism*
- Transfection
Substances
- DNA-Binding Proteins
- Intracellular Signaling Peptides and Proteins
- RNA, Messenger
- RNA, Small Interfering
- STAT3 Transcription Factor
- STAT3 protein, human
- Trans-Activators
- DNA Modification Methylases
- DNA (Cytosine-5-)-Methyltransferase 1
- DNA (Cytosine-5-)-Methyltransferases
- DNMT1 protein, human
- PTPN6 protein, human
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
- Protein Tyrosine Phosphatases
- HDAC1 protein, human
- Histone Deacetylase 1
- Histone Deacetylases