Abstract
Zinc finger protein 554 (ZNF554), a member of the Krüppel-associated box domain zinc finger protein subfamily, is predominantly expressed in the brain and placenta in humans. Recently, we unveiled that ZNF554 regulates trophoblast invasion during placentation and its decreased expression leads to the early pathogenesis of preeclampsia. Since ZNF proteins are immensely implicated in the development of several tumors including malignant tumors of the brain, here we explored the pathological role of ZNF554 in gliomas. We examined the expression of ZNF554 at mRNA and protein levels in normal brain and gliomas, and then we searched for genome-wide transcriptomic changes in U87 glioblastoma cells transiently overexpressing ZNF554. Immunohistochemistry of brain tissues in our cohort (n = 62) and analysis of large TCGA RNA-Seq data (n = 687) of control, oligodendroglioma, and astrocytoma tissues both revealed decreased expression of ZNF554 towards higher glioma grades. Furthermore, low ZNF554 expression was associated with shorter survival of grade III and IV astrocytoma patients. Overexpression of ZNF554 in U87 cells resulted in differential expression, mostly downregulation of 899 genes. The “PI3K-Akt signaling pathway”, known to be activated during glioma development, was the most impacted among 116 dysregulated pathways. Most affected pathways were cancer-related and/or immune-related. Congruently, cell proliferation was decreased and cell cycle was arrested in ZNF554-transfected glioma cells. These data collectively suggest that ZNF554 is a potential tumor suppressor and its decreased expression may lead to the loss of oncogene suppression, activation of tumor pathways, and shorter survival of patients with malignant glioma.
Highlights
Zinc-finger proteins (ZNFs) belong to one of the largest transcription factor families in the human genome showing a great diversity of molecular functions [1]
Zinc finger protein 554 (ZNF554) overexpression in U87 glioblastoma cells leads to dysregulation of several pathways and genes known to be impacted in adult diffuse gliomas. These results suggest that ZNF554 is a potential tumor suppressor and its decreased expression may lead to the activation of tumor pathways in adult diffuse gliomas, with a detrimental effect on patient survival
Principal Findings of This Study: (1) ZNF554 shows predominant brain expression with low region specificity in humans; (2) in adult diffuse gliomas, ZNF554 mRNA and protein expressions decrease with increasing tumor grade; (3) low ZNF554 mRNA expression is associated with shorter survival of anaplastic astrocytoma and glioblastoma patients, and when all gliomas are analyzed together; (4) the overexpression of ZNF554 results in the dysregulation of 899 genes in U87 glioblastoma cells, and most of these are downregulated; (5) among 116 dysregulated pathways, 73 are cancer-related and 86 are immune-related (49 pathways are common), and these are mostly downregulated; and (6) the overexpression of ZNF554 decreases cell proliferation and induces cell cycle arrest
Summary
Zinc-finger proteins (ZNFs) belong to one of the largest transcription factor families in the human genome showing a great diversity of molecular functions [1]. One-third of ZNFs belong to the Krüppel-associated box domain zinc finger protein (KRAB-ZNF) subfamily and contribute to transcriptional regulation during various cellular processes including differentiation, cell growth, and morphogenesis [7,8,9]. Our recent tissue qRT-PCR study revealed that ZNF554 gene expression is mostly restricted to the brain and placenta in humans [13]. Our genome-wide transcriptomic analysis showed the emerging role of ZNF554 as a hub transcription factor that drives deep trophoblast invasion, and the pathogenesis of preeclampsia is partly originated from its dysregulation. ZNF554-silenced extravillous trophoblast cells had reduced migratory and invasive functions [13]
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