STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes

Qian Zhang, Hong Y. Wang, Michal Marzec, Puthiyaveettil N. Raghunath, Tomohiko Nagasawa, Mariusz A. Wasik

Research output: Contribution to journalArticlepeer-review

224 Scopus citations

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 languageEnglish
Pages (from-to)6948-6953
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number19
DOIs
StatePublished - 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

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