Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer.
Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer.
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DOI：
10.1038/onc.2015.296
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发表时间：
2016-05-05
期刊：
影响因子：
8
通讯作者：
Wang YC
中科院分区：
文献类型：
--
作者：
Jen J;Lin LL;Chen HT;Liao SY;Lo FY;Tang YA;Su WC;Salgia R;Hsu CL;Huang HC;Juan HF;Wang YC
编码经典 Cys2His2 锌指转录因子的 ZNF322A 先前被揭示为肺癌患者的潜在癌基因。然而，ZNF322A 的致癌作用及其在肺肿瘤发生中的潜在机制仍不清楚。在这里，我们显示了 123 名亚洲人和 74 名白种人肺癌患者中 ZNF322A 蛋白过度表达。多变量Cox回归分析表明ZNF322A是肺癌预后不良的独立危险因素，证实了Kaplan-Meier结果，即ZNF322A蛋白过度表达的患者总体生存率明显低于其他患者。 ZNF322A 的过表达通过延长多种肺细胞系（包括永生化肺细胞 BEAS-2B）中 S 期的细胞周期来促进细胞增殖和软琼脂生长。此外，ZNF322A过表达增强细胞迁移和侵袭，而ZNF322A敲低则降低细胞体外和体内生长、侵袭和转移能力。定量蛋白质组学分析揭示了 ZNF322A 调节的潜在下游靶标，包括 α-内收蛋白 (ADD1)、细胞周期蛋白 D1 (CCND1) 和 p53。利用荧光素酶启动子活性测定结合定点诱变和序贯染色质免疫沉淀-PCR测定，我们发现ZNF322A可以与c-Jun形成复合物并协同激活ADD1和CCND1，但通过以AP-1元件依赖性方式招募差异染色质修饰剂（例如组蛋白脱乙酰酶3）来抑制p53基因转录。重建实验表明CCND1和p53对于ZNF322A介导的细胞增殖促进很重要，而ADD1对于ZNF322A介导的细胞迁移和侵袭是必需的。我们的结果提供了令人信服的证据，证明 ZNF322A 过度表达会导致细胞生长和运动相关基因转录失调，从而导致肺肿瘤发生和不良预后。
ZNF322A encoding a classical Cys2His2 zinc finger transcription factor was previously revealed as a potential oncogene in lung cancer patients. However, the oncogenic role of ZNF322A and its underlying mechanism in lung tumorigenesis remain elusive. Here we show ZNF322A protein overexpression in 123 Asian and 74 Caucasian lung cancer patients. Multivariate Cox regression analysis indicated that ZNF322A was an independent risk factor for a poor outcome in lung cancer, corroborating the Kaplan–Meier results that patients with ZNF322A protein overexpression had significantly poorer overall survival than other patients. Overexpression of ZNF322A promoted cell proliferation and soft agar growth by prolonging cell cycle in S phase in multiple lung cell lines, including the immortalized lung cell BEAS-2B. In addition, ZNF322A overexpression enhanced cell migration and invasion, whereas knockdown of ZNF322A reduced cell growth, invasion and metastasis abilities in vitro and in vivo. Quantitative proteomic analysis revealed potential ZNF322A-regulated downstream targets, including alpha-adducin (ADD1), cyclin D1 (CCND1), and p53. Using luciferase promoter activity assay combined with site-directed mutagenesis and sequential chromatin immunoprecipitation-PCR assay, we found that ZNF322A could form a complex with c-Jun and cooperatively activate ADD1 and CCND1 but repress p53 gene transcription by recruiting differential chromatin modifiers, such as histone deacetylase 3, in an AP-1 element dependent manner. Reconstitution experiments indicated that CCND1 and p53 were important to ZNF322A-mediated promotion of cell proliferation, whereas ADD1 was necessary for ZNF322A-mediated cell migration and invasion. Our results provide compelling evidence that ZNF322A overexpression transcriptionally dysregulates genes involved in cell growth and motility therefore contributes to lung tumorigenesis and poor prognosis.