Wang Lei, Devarajan Eswaran, He Jin, Reddy Sekhar P, Dai Jia Le
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2005 Nov 15;65(22):10289-97. doi: 10.1158/0008-5472.CAN-05-2231.
Spleen tyrosine kinase (SYK) is a candidate tumor suppressor gene in breast. Loss of SYK expression in breast tumors as a result of DNA hypermethylation promotes tumor cell proliferation and invasion and predicts shorter survival of breast cancer patients. We previously reported that, in addition to its well-known cytoplasmic localization, the full-length Syk is also present in the nucleus and that Syk nuclear translocation is a rate-limiting step to determine Syk tumor suppressor function. Here, we show that the full-length form of Syk acts as a transcription repressor in the cell nucleus. Ectopic expression of Syk down-regulates the transcription of FRA1 and cyclin D1 oncogenes. This transcription-repressing activity of Syk is associated with its binding to members of the histone deacetylase family. Syk interacts with transcription factor Sp1 at the Sp1 DNA-binding site in the FRA1 promoter to repress Sp1-activated FRA1 transcription. Thus, breast tumorigenesis and progression resulting from the loss of SYK are underscored by the derepression of Sp1-mediated oncogene transcription.
脾酪氨酸激酶（SYK）是乳腺癌中的一个候选肿瘤抑制基因。由于DNA高甲基化导致乳腺肿瘤中SYK表达缺失，会促进肿瘤细胞增殖和侵袭，并预示着乳腺癌患者生存期较短。我们之前报道过，除了其众所周知的细胞质定位外，全长Syk也存在于细胞核中，并且Syk核转位是决定Syk肿瘤抑制功能的限速步骤。在此，我们表明全长形式的Syk在细胞核中充当转录抑制因子。Syk的异位表达下调FRA1和细胞周期蛋白D1癌基因的转录。Syk的这种转录抑制活性与其与组蛋白脱乙酰酶家族成员的结合有关。Syk在FRA1启动子中的Sp1 DNA结合位点与转录因子Sp1相互作用，以抑制Sp1激活的FRA1转录。因此，Sp1介导的癌基因转录去抑制突出了因SYK缺失导致的乳腺肿瘤发生和进展。
