Volume 31 Issue 1 - November 4, 2016 PDF
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Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer
Jayu Jen1, Li-Ling Lin2, Hsiung-Ting Chen3, Sheng-You Liao1, Fang-Yi Lo3, Yen-An Tang3, Wu-Chou Su4, Ravi Salgia5, Chia-Lang Hsu2, Hsuan-Cheng Huang6, Hsueh-Fen Juan2, Yi-Ching Wang1,3,*
1 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2 Department of Life Science, Institute of Molecular and Cellular Biology, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
3 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4 Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5 Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
6 Institute of Biomedical Informatics and Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan
 
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Lung cancer is the leading cause of cancer-associated death worldwide. To elucidate the underlying tumorigenic mechanism in lung cancer, we previously conducted array-comparative genomic hybridization assay and identified ZNF322A as a potential oncogene in both Asian and Caucasian lung cancer patients. ZNF322A encodes a transcription factor consisting of 11 tandem repeats of zinc finger motif, however, its transcriptional mechanism and oncogenic role has never been reported. In the current study, we show that overexpression of ZNF322A promotes lung cancer cell proliferation, migration and invasion abilities both in vitro and in vivo. To clarify the underlying mechanism of ZNF322A in lung cancer, we perform quantitative proteomics and identify three putative ZNF322A downstream targets, including alpha-adducin (ADD1), cyclin D1 (CCND1) and p53. Mechanistically, our results reveal that ZNF322A interacts with c-Jun and cooperatively upregulates ADD1 and CCND1 expression but downregulates p53 expression through AP-1 elements. To further unveil the differential regulation of ZNF322A on downstream genes, we conduct chromatin immunoprecipitation-qPCR assay to find that, different from that on ADD1 and CCND1 promoters, ZNF322A recruits histone deacetylase 3 to p53 promoter, decreases active chromatin marker acetylated histone 3, and therefore leads to p53 suppression (Figure 1). To confirm the clinical significance of ZNF322A and its relationship with downstream targets, immunohistochemistry was performed to show that ZNF322A overexpression coordinates with overexpression of ADD1 and CCND1 along with downregulation of p53 protein expression (Figure 2A). In contrast, patients with normal ZNF322A expression show low expression of ADD1 and CCND1 and positive immunostaining for p53 (Figure 2B). Notably, patients with ZNF322A protein overexpression show poorer overall survival (Figure 2C). Our results provide first evidence that overexpression of ZNF322A contributes to lung tumorigenesis and poor prognosis, which partly mediated through deregulation of ADD1, CCND1 and p53 at transcription level.
Figure 1. Schematic representation of ZNF322A differential regulation on downstream genes, ADD1, CCND1 and p53, and subsequent promotion of cell proliferation, tumor metastasis and poor prognosis. ZNF322A forms a complex with c-Jun and cooperative targets to AP-1 elements on downstream gene promoter regions. Through recruiting different chromatin modifiers, ZNF322A can positively regulate the expression of ADD1 and CCND1 but negatively regulate the expression of p53, and eventually lead to lung tumorigenesis.
Figure 2. Clinical significance of ZNF322A overexpression in lung cancer patients. (A, B) The representative immunohistochemistry figures for ZNF322A, ADD1, CCND1 and p53 protein in tumor specimen are shown for two lung cancer patients. (C) Kaplan-Meier curves showing lung cancer patients with ZNF322A protein overexpression (solid line) had significantly poorer overall survival than those with normal expression (dotted line). P values for survival analyses were determined using log-rank test.
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