Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer

Abstract

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.

Overexpression of zinc finger protein 687 enhances tumorigenic capability and promotes recurrence of hepatocellular carcinoma

“… 7 , 10 , 25 , 26 However, the critical factors that regulate CSC maintenance in HCC remain largely unknown. Recent studies have revealed that aberrant expression of zinc finger proteins contributes to progression in multiple cancers, including tumorigenicity, metastasis and chemoresistance, 27 , 28 , 29 which the CSC subpopulation might regulate. Here, we found that ZNF687 overexpression markedly promoted HCC cell tumorsphere formation capability and increased the HCC SP + /CD133 + populations in vitro .…”

Adducin in tumorigenesis and metastasis

“…They found that ZNF322A formed a complex with c-Jun and cooperatively activated ADD1 and CCND1 but repressed p53 gene transcription. 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, suggesting ADD1 was involved in tumorigenesis and metastasis of lung cancer [ 45 ].…”

p53 protein expression affected by TP53 polymorphism is associated with the biological behavior and prognosis of low rectal cancer

“…As a subtype of colorectal cancer at a special anatomical site, LRC is characterized by its specific biological behavior. TP53 is one of the most important cancer suppressor genes, and structural variation and abnormal expression of p53 have been identified to be associated with numerous cancer types (22)(23)(24)(25). However, the associations between TP53 gene polymorphisms and protein expression, and the association of p53 protein expression with the biological behavior and prognosis of LRC have not been clearly investigated.…”