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PNAS 102 (19): 6948-6953

Copyright © 2005 by the National Academy of Sciences.


MEDICAL SCIENCES

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, and Mariusz A. Wasik *

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104

Communicated by Peter C. Nowell, University of Pennsylvania School of Medicine, Philadelphia, PA, March 9, 2005

Received for publication January 10, 2005.

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.

Key Words: DNMT1 • SHP-1 • STAT3


Author contributions: Q.Z. and M.A.W. designed research; Q.Z., H.Y.W., M.M., P.N.R., and T.N. performed research; and M.A.W. wrote the paper.

Abbreviations: ALK+ TCL, T cell lymphoma expressing anaplastic lymphoma kinase; ChIP, chromatin immunoprecipitation; CTCL, cutaneous T-cell lymphoma; DNMT, DNA methyltransferase; HDAC, histone deacetylase; ON, oligonucleotide; PBMC; peripheral blood mononuclear cells; PHA-BL, phytohemagglutinin-activated T cell blasts; siRNA, small interfering RNA; STAT, signal transducer and activator of transcription.

* To whom correspondence should be addressed. E-mail: wasik{at}mail.med.upenn.edu.

© 2005 by The National Academy of Sciences of the USA


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