KRAB Zinc Finger Protein ZNF382 Is a Proapoptotic Tumor Suppressor That Represses Multiple Oncogenes and Is Commonly Silenced in Multiple Carcinomas
KRAB Zinc Finger Protein ZNF382 Is a Proapoptotic Tumor Suppressor That Represses Multiple Oncogenes and Is Commonly Silenced in Multiple Carcinomas
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DOI：
10.1158/0008-5472.can-09-4566
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发表时间：
2010-08-15
期刊：
影响因子：
11.2
通讯作者：
Tao, Qian
中科院分区：
文献类型：
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作者：
Cheng, Yingduan;Geng, Hua;Tao, Qian
锌指转录因子广泛参与发育和肿瘤发生。在这里，我们报告，很少研究锌指转录因子ZNF 382作为一个肿瘤抑制因子在多种癌症。虽然ZNF 382在正常组织中广泛表达，但由于启动子CpG甲基化，ZNF 382在多种癌细胞系中的表达减弱。ZNF 382在多种原发性肿瘤（鼻咽、食管、结肠、胃和乳腺）中也经常甲基化。ZNF 382在沉默的肿瘤细胞中的异位表达显著抑制其克隆形成和增殖，并诱导凋亡。我们进一步发现，ZNF 382抑制NF-κ B和AP-1信号传导，下调多种癌基因的表达，包括MYC、MITF、HMGA 2和CDK 6，以及NF-κ B上游因子STAT 3、STAT 5 B、ID 1和IKBKE，最有可能是通过异染色质沉默。ZNF 382可通过异染色质介导的沉默抑制肿瘤的发生，因为ZNF 382与异染色质蛋白HP 1共定位并相互作用，并进一步改变ZNF 382靶癌基因的染色质修饰。我们的数据表明，ZNF 382是一种功能性肿瘤抑制因子，在多种肿瘤中经常发生甲基化。Cancer Res; 70（16）; 6516-26.（C）2010年AACR。
Zinc finger transcription factors are involved broadly in development and tumorigenesis. Here, we report that the little studied zinc finger transcription factor ZNF382 functions as a tumor suppressor in multiple carcinomas. Although broadly expressed in normal tissues, ZNF382 expression was attenuated in multiple carcinoma cell lines due to promoter CpG methylation. ZNF382 was also frequently methylated in multiple primary tumors (nasopharyngeal, esophageal, colon, gastric, and breast). Ectopic expression of ZNF382 in silenced tumor cells significantly inhibited their clonogenicity and proliferation and induced apoptosis. We further found that ZNF382 inhibited NF-kappa B and AP-1 signaling and downregulated the expression of multiple oncogenes including MYC, MITF, HMGA2, and CDK6, as well as the NF-kappa B upstream factors STAT3, STAT5B, ID1, and IKBKE, most likely through heterochromatin silencing. ZNF382 could suppress tumorigenesis through heterochromatin-mediated silencing, as ZNF382 was colocalized and interacted with heterochromatin protein HP1 and further changed the chromatin modifications of ZNF382 target oncogenes. Our data show that ZNF382 is a functional tumor suppressor frequently methylated in multiple carcinomas. Cancer Res; 70(16); 6516-26. (C)2010 AACR.