Decreased Expression of ZNF554 in Gliomas is Associated with the Activation of Tumor Pathways and Shorter Patient Survival

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.

Zinc Finger Proteins in Neuro-Related Diseases Progression

“…Like zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) from C2H2 type, downregulation of ZKSCAN3 is observed in aged human mesenchymal stem cells (hMSCs) and depletion of ZKSCAN3 accelerates senescence of these cells ( Hu et al, 2020 ; Turelli et al, 2020 ). ZNF also play an important role in brain tumor disease ( Balogh et al, 2020 ; Liang et al, 2020 ; Natsumeda et al, 2021 ; Okado, 2021 ). The AN1/A20 zinc finger domain containing protein 3 (ZFAND3) as a crucial driver of glioblastoma invasion.…”

ZNF655 promotes the progression of hepatocellular carcinoma through PSMB8

“…Additionally, reduced expression of ZNF233 in HCC inhibits cell proliferation and tumorigenesis (Xie et al, 2018). In contrast, ZNF554 is regarded as a potential tumor suppressor in malignant gliomas, and its reduced expression may lead to the loss of oncogene suppression and the activation of tumor pathways (Balogh et al, 2020). Moreover, ZNF655, discovered from yeast and also known as Vav-interacting Kruppel-like protein-1 (Vik-1), belongs to the C2H2-type ZNF (Houlard et al, 2005).…”

ZNF655 accelerates progression of pancreatic cancer by promoting the binding of E2F1 and CDK1

“…In addition, reduced expression of ZNF233 in hepatocellular carcinoma inhibits cell proliferation and tumorigenesis [21]. In contrast, ZNF554 is regarded as a potential tumor suppressor in malignant gliomas, and its reduced expression may lead to the loss of oncogene suppression and the activation of tumor pathways [22]. As a transcription factor of Cys2His2 type ZNF, the role of ZNF655 in pancreatic cancer has not been reported.…”