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

Proc Natl Acad Sci U S A. 2005 May 10;102(19):6948-53. doi: 10.1073/pnas.0501959102. Epub 2005 May 3.

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