Document Detail


STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes.
MedLine Citation:
PMID:  16861352     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we demonstrated that STAT3, a well-characterized transcription factor expressed in continuously activated oncogenic form in the large spectrum of cancer types, induces in malignant T lymphocytes the expression of DNMT1, the key effector of epigenetic gene silencing. STAT3 binds in vitro to 2 STAT3 SIE/GAS-binding sites identified in promoter 1 and enhancer 1 of the DNMT1 gene. STAT3 also binds to the promoter 1 region and induces its activity in vivo. Treatment of the malignant T lymphocytes with STAT3 siRNA abrogates expression of DNMT1, inhibits cell growth, and induces programmed cell death. In turn, inhibition of DNMT1 by a small molecule inhibitor, 5-aza-2-deoxy-cytidine, and 2 DNMT1 antisense DNA oligonucleotides inhibits the phosphorylation of STAT3. These data indicate that STAT3 may in part transform cells by fostering epigenetic silencing of tumor-suppressor genes. They also indicate that by inducing DNMT1, STAT3 facilitates its own persistent activation in malignant T cells. Finally, these data provide further rationale for therapeutically targeting STAT3 in T-cell lymphomas and, possibly, other malignancies.
Authors:
Qian Zhang; Hong Y Wang; Anders Woetmann; Puthiyaveettil N Raghunath; Niels Odum; Mariusz A Wasik
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Blood     Volume:  108     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-07-24     Completed Date:  2006-10-05     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1058-64     Citation Subset:  AIM; IM    
Affiliation:
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 7.103 Founders, Philadelphia, 19104, USA. qian2@mail.med.upenn.edu
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MeSH Terms
Descriptor/Qualifier:
Apoptosis
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
DNA (Cytosine-5-)-Methyltransferase / genetics*,  physiology
Epigenesis, Genetic
Gene Silencing
Humans
Lymphoma, T-Cell / enzymology,  metabolism*,  pathology
Phosphorylation
STAT3 Transcription Factor / metabolism,  physiology*
T-Lymphocytes / enzymology,  metabolism,  pathology
Transcription, Genetic*
Tumor Suppressor Proteins / genetics
Grant Support
ID/Acronym/Agency:
R01-CA89194/CA/NCI NIH HHS; R01-CA96856/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/STAT3 Transcription Factor; 0/STAT3 protein, human; 0/Tumor Suppressor Proteins; EC 2.1.1.37/DNA (Cytosine-5-)-Methyltransferase; EC 2.1.1.37/DNA (cytosine-5-)-methyltransferase 1
Comments/Corrections

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