https://scholars.lib.ntu.edu.tw/handle/123456789/582960
標題: | Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer | 作者: | Jen J. Lin L.-L. Chen H.-T. Liao S.-Y. Lo F.-Y. Tang Y.-A. Su W.-C. Salgia R. CHIA-LANG HSU Huang H.-C. Juan H.-F. Wang Y.-C. |
公開日期: | 2016 | 出版社: | Nature Publishing Group | 卷: | 35 | 期: | 18 | 起(迄)頁: | 2357-2369 | 來源出版物: | Oncogene | 摘要: | 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. ? 2016 Macmillan Publishers Limited All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84939442333&doi=10.1038%2fonc.2015.296&partnerID=40&md5=b1d8c30472b7bfda3244f01362336d50 https://scholars.lib.ntu.edu.tw/handle/123456789/582960 |
ISSN: | 0950-9232 | DOI: | 10.1038/onc.2015.296 | SDG/關鍵字: | alpha adducin; cyclin D1; histone deacetylase 3; oncoprotein; protein c jun; protein p53; transcription factor AP 1; unclassified drug; zinc finger protein; ZNF322A protein; adducin; calmodulin binding protein; chromatin; cyclin D1; DNA binding protein; protein p53; stress activated protein kinase; transcription factor; transcription factor AP 1; ZNF323 protein, human; aged; Article; Asian; cancer growth; cancer prognosis; cancer risk; cancer survival; Caucasian; cell cycle S phase; cell migration; cell proliferation; chromatin immunoprecipitation; controlled study; female; gene overexpression; genetic transcription; human; immortalized cell line; in vitro study; in vivo study; luciferase assay; lung cancer; lung cancer cell line; lung carcinogenesis; major clinical study; male; metastasis; overall survival; polymerase chain reaction; priority journal; protein expression; proteomics; quantitative analysis; site directed mutagenesis; transcription regulation; tumor invasion; cell motion; chromatin; genetic transcription; genetics; Lung Neoplasms; metabolism; metastasis; middle aged; pathology; prognosis; promoter region; tumor cell line; Aged; Calmodulin-Binding Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromatin; Cyclin D1; DNA-Binding Proteins; Female; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Promoter Regions, Genetic; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Tumor Suppressor Protein p53 |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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