STAT3- and DNA Methyltransferase 1-Mediated Epigenetic Silencing of SHP-1 Tyrosine Phosphatase Tumor Suppressor Gene in Malignant T Lymphocytes

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 19; pp. 6948 - 6953
• Main Authors: Zhang, Qian, Wang, Hong Y., Marzec, Michal, Raghunath, Puthiyaveettil N., Nagasawa, Tomohiko, Wasik, Mariusz A., Nowell, Peter C.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.05.2005; National Acad Sciences
• Subjects: Antibodies; Base Sequence; Binding sites; Biological Sciences; Blotting, Western; Cell Line, Tumor; Cell lines; Chromatin Immunoprecipitation; CpG Islands; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA Modification Methylases - metabolism; DNA-Binding Proteins - metabolism; Down-Regulation; Enzymes; Epigenetics; Gene Silencing; Genes; Histone Deacetylase 1; Histone Deacetylases - metabolism; Humans; Immunohistochemistry; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Lymphoma; Lymphoma, T-Cell - metabolism; Medical research; Methylation; Models, Genetic; Molecular Sequence Data; Polymerase chain reaction; Promoter Regions, Genetic; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Signal transduction; STAT3 Transcription Factor; T cell lymphoma; T lymphocytes; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; Trans-Activators - metabolism; Transfection
• DOI: 10.1073/pnas.0501959102
• ISSN: 0027-8424

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.