STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes
STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes
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DOI：
10.1182/blood-2005-08-007377
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发表时间：
2006-08-01
期刊：
影响因子：
20.3
通讯作者：
Wasik, Mariusz A.
中科院分区：
文献类型：
--
作者：
Zhang, Qian;Wang, Hong Y.;Wasik, Mariusz A.
在这项研究中，我们证明，STAT 3，一个良好的特征转录因子表达的连续激活致癌形式在大范围的癌症类型，诱导恶性T淋巴细胞的DNMT 1的表达，表观遗传基因沉默的关键效应。STAT 3在体外与DNMT 1基因的启动子1和增强子1中鉴定的2个STAT 3 SIE/GAS结合位点结合。STAT 3还结合启动子1区并诱导其体内活性。用STAT 3 siRNA处理恶性T淋巴细胞可消除DNMT 1的表达，抑制细胞生长，并诱导程序性细胞死亡。反过来，通过小分子抑制剂5-氮杂-2-脱氧胞苷和2种DNMT 1反义DNA寡核苷酸抑制DNMT 1抑制STAT 3的磷酸化。这些数据表明，STAT 3可能在一定程度上通过促进肿瘤抑制基因的表观遗传沉默来转化细胞。他们还表明，通过诱导DNMT 1，STAT 3促进其自身在恶性T细胞中的持续激活。最后，这些数据为T细胞淋巴瘤以及可能的其他恶性肿瘤的治疗靶向STAT 3提供了进一步的理论基础。
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.