TY - JOUR

T1 - STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes

AU - Zhang, Qian

AU - Wang, Hong Y

AU - Woetmann, Anders

AU - Raghunath, Puthiyaveettil N

AU - Odum, Niels

AU - Wasik, Mariusz A

N1 - Keywords: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; DNA (Cytosine-5-)-Methyltransferase; Epigenesis, Genetic; Gene Silencing; Humans; Lymphoma, T-Cell; Phosphorylation; STAT3 Transcription Factor; T-Lymphocytes; Transcription, Genetic; Tumor Suppressor Proteins

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1182/blood-2005-08-007377

DO - 10.1182/blood-2005-08-007377

M3 - Journal article

C2 - 16861352

VL - 108

SP - 1058

EP - 1064

JO - Blood

JF - Blood

SN - 0006-4971

IS - 3

ER -