Abstract
BackgroundZinc-finger protein-326 (ZNF326) was initially found in the NIH3T3 cell line to regulate cell growth, however, the expression and underlying role of ZNF326 in human tumours, especially in glioma, is not fully understood.MethodsImmunohistochemistry was applied to detect the expression of ZNF326 in glioma tissues, and statistical analysis was used to analyse the relationship between ZNF326 expression and clinicopathological factors. The effect of ZNF326 on glioma cells proliferation and invasion was conducted by functional experiments both in vivo and in vitro. Chromatin immunoprecipitation and dual-luciferase assays were performed to demonstrate that histone deacetylase enzyme-7 (HDAC7) is the target gene of ZNF326. Immunoblotting, real-time PCR, GST-pulldown and co-immunoprecipitation assays were used to clarify the underlying role of ZNF326 on Wnt pathway activation.ResultsHigh nuclear expression of ZNF326 was observed in glioma cell lines and tissues, and closely related with advanced tumour grade in the patients. Moreover, ectopic ZNF326 expression promoted the proliferation and invasiveness of glioma cells. Mechanistically, ZNF326 could activate HDAC7 transcription by binding to a specific promoter region via its transcriptional activation domain and zinc-finger structures. The interaction of the up-regulated HDAC7 with β-catenin led to a decrease in β-catenin acetylation level at Lys-49, followed by a decrease in β-catenin phosphorylation level at Ser-45. These changes in β-catenin posttranscriptional modification levels promoted its redistribution and import into the nucleus. Additionally, ZNF326 directly associated with β-catenin in the nucleus, and enhanced the binding of β-catenin to TCF-4, serving as a co-activator in stimulating Wnt pathway.ConclusionsOur findings elucidated ZNF326 promotes the malignant phenotype of human glioma via ZNF326-HDAC7-β-catenin signalling. This study reveals the vital role and mechanism of ZNF326 in the malignant progression of glioma, and provides the reference for finding biomarkers and therapeutic targets for glioma.
Highlights
Zinc-finger protein-326 (ZNF326) was initially found in the NIH3T3 cell line to regulate cell growth, the expression and underlying role of ZNF326 in human tumours, especially in glioma, is not fully understood
ZNF326 is highly expressed in glioma and positively correlated with tumour grade To explore a potential role of ZNF326 in glioma tumorigenesis, we performed IHC in a cohort of 133 human patients with glioma samples to examine the expression profiles of ZNF326
We found that nearly 60.9% (81/ 133) of patients with glioma had high level of nuclear ZNF326 (+, ++ and +++) in the glioma samples
Summary
Zinc-finger protein-326 (ZNF326) was initially found in the NIH3T3 cell line to regulate cell growth, the expression and underlying role of ZNF326 in human tumours, especially in glioma, is not fully understood. Current therapeutic strategies for glioma consist of neurosurgical resection, chemotherapy, and radiotherapy. All these strategies have failed to yield an expected good prognosis of malignant glioma. This could be due to the highly aggressive nature of glioma cells that are capable of infiltrating into the adjacent normal brain tissue [4, 5]. There is always an urgency to develop novel strategies for timely diagnosis and therapeutic agents for patients with glioma. The Wnt pathway elicits an important regulatory signal that is able to influence embryonic development of different tissues and organs, including the nervous system.
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