A Novel 19q13 Nucleolar Zinc Finger Protein Suppresses Tumor Cell Growth through Inhibiting Ribosome Biogenesis and Inducing Apoptosis but Is Frequently Silenced in Multiple Carcinomas
A Novel 19q13 Nucleolar Zinc Finger Protein Suppresses Tumor Cell Growth through Inhibiting Ribosome Biogenesis and Inducing Apoptosis but Is Frequently Silenced in Multiple Carcinomas
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一种新型 19q13 核仁锌指蛋白通过抑制核糖体生物发生和诱导细胞凋亡来抑制肿瘤细胞生长，但在多种癌症中经常被沉默
DOI：
10.1158/1541-7786.mcr-11-0594
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发表时间：
2012-07-01
影响因子：
5.2
通讯作者：
Tao, Qian
中科院分区：
文献类型：
--
作者：
Cheng, Yingduan;Liang, Pei;Tao, Qian
肿瘤抑制基因的表观遗传学破坏经常参与肿瘤的发生。我们鉴定了一种新的19 q13 KRAB结构域锌指蛋白ZNF 545/ZFP 82，其在正常组织中广泛表达，但在多种肿瘤细胞系中下调。ZNF 545启动子含有CpG岛，其在细胞系中经常被甲基化。ZNF 545的转录沉默可以通过药物或遗传去甲基化来逆转，表明直接的表观遗传沉默。ZNF 545在鼻咽、食管、肺、胃、结肠和乳腺的多原发肿瘤中也经常发生甲基化，但在正常上皮组织和配对正常组织中很少发生甲基化。ZNF 545位于细胞核内，主要分布在核仁中，起阻遏蛋白的作用。ZNF 545能够抑制NF-κB和AP-1信号通路，而ZNF 545在沉默的肿瘤细胞中的异位表达显著抑制肿瘤细胞的生长并诱导凋亡。功能研究表明，ZNF 545通过抑制rDNA启动子活性和降低细胞蛋白质翻译效率参与核糖体的生物合成。因此，我们确定ZNF 545是一个新的肿瘤抑制剂，它能诱导肿瘤细胞凋亡，抑制核糖体的生物合成和靶基因的转录。ZNF 545的肿瘤特异性甲基化可能是肿瘤诊断的表观遗传学生物标志物。Mol Cancer Res; 10（7）; 925-36.©2012 AACR。
Epigenetic disruption of tumor suppressor genes is frequently involved in tumorigenesis. We identified a novel 19q13 KRAB domain-containing zinc finger protein, ZNF545/ZFP82, broadly expressed in normal tissues but downregulated in multiple tumor cell lines. The ZNF545 promoter contains a CpG island, which is frequently methylated in cell lines. The transcriptional silencing of ZNF545 could be reversed by pharmacologic or genetic demethylation, indicating direct epigenetic silencing. ZNF545 was also frequently methylated in multiple primary tumors of nasopharyngeal, esophageal, lung, gastric, colon, and breast, but rarely in normal epithelial tissues and paired normal tissues. ZNF545 is located in the nucleus and mainly sequestered in nucleoli, functioning as a repressor. ZNF545 is able to repress NF-κB and AP-1 signaling pathways, whereas ectopic expression of ZNF545 in silenced tumor cells significantly inhibited their growth and induced apoptosis. Functional studies showed that ZNF545 was involved in ribosome biogenesis through inhibiting the activity of rDNA promoter and decreasing cellular protein translation efficiency. Thus, we identified ZNF545 as a novel tumor suppressor inducing tumor cell apoptosis, repressing ribosome biogenesis and target gene transcription. The tumor-specific methylation of ZNF545 could be an epigenetic biomarker for cancer diagnosis. Mol Cancer Res; 10(7); 925–36. ©2012 AACR.