Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, China.
Mol Cancer Res. 2012 Jul;10(7):925-36. doi: 10.1158/1541-7786.MCR-11-0594. Epub 2012 Jun 7.
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.
表观遗传抑制肿瘤抑制基因经常涉及肿瘤发生。我们鉴定了一种新型的 19q13 KRAB 结构域包含锌指蛋白，ZNF545/ZFP82，在正常组织中广泛表达，但在多种肿瘤细胞系中下调。ZNF545 启动子包含一个 CpG 岛，在细胞系中经常甲基化。ZNF545 的转录沉默可以通过药物或遗传去甲基化逆转，表明直接的表观遗传沉默。ZNF545 也在多个鼻咽癌、食管癌、肺癌、胃癌、结肠癌和乳腺癌的原发性肿瘤中经常甲基化，但在正常上皮组织和配对的正常组织中很少见。ZNF545 位于细胞核内，主要定位于核仁，作为一种抑制物。ZNF545 能够抑制 NF-κB 和 AP-1 信号通路，而沉默肿瘤细胞中外源表达 ZNF545 显著抑制其生长并诱导细胞凋亡。功能研究表明，ZNF545 通过抑制 rDNA 启动子的活性和降低细胞蛋白翻译效率来参与核糖体生物发生。因此，我们鉴定了 ZNF545 作为一种诱导肿瘤细胞凋亡、抑制核糖体生物发生和靶基因转录的新型肿瘤抑制因子。ZNF545 的肿瘤特异性甲基化可能是癌症诊断的一种表观遗传生物标志物。
