Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer.
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.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
J
J
Jen
Department of Life Science, Institute of Molecular and Cellular Biology, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
L-L
LL
Lin
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
H-T
HT
Chen
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
S-Y
SY
Liao
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
F-Y
FY
Lo
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Y-A
YA
Tang
Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
W-C
WC
Su
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
R
R
Salgia
Department of Life Science, Institute of Molecular and Cellular Biology, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
C-L
CL
Hsu
Institute of Biomedical Informatics and Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan.
H-C
HC
Huang
Department of Life Science, Institute of Molecular and Cellular Biology, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
H-F
HF
Juan
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Y-C
YC
Wang
D000368:Aged; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D002843:Chromatin; D019938:Cyclin D1; D004268:DNA-Binding Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000099291:Adducins; C464855:ZSCAN31 protein, human