Zinc finger protein 852 is essential for the proliferation, drug sensitivity, and self‐renewal of gastric cancer cells

Abstract

Exploring cellular and molecular mechanisms responsible for gastric cancer growth, survival, self-renewal, and metastasis helps develop efficacious therapeutic strategies. In this study, the expression and function of zinc finger protein 852 (ZNF852) in human gastric cancer cell lines were characterized. ZNF852 was upregulated in gastric cancer cell lines relative to normal gastric epithelial cell line GES-1. When the ZNF852 gene was ablated in gastric cancer cell line MGC-803 using the CRISPR/ Cas9-encoding lentivirus, the proliferation of MGC-803 was suppressed. ZNF852 deficiency also resulted in the inhibition of MGC-803 sphere formation, along with decreases in SRY-box 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and Nanog homeobox (NANOG), suggesting that ZNF852 sustains self-renewal of MGC-803 cells. Furthermore, ZNF852 deficiency increased oxaliplatin-induced MGC-803 cell death, implying the role of ZNF852 in drug sensitivity. Subcutaneous infusion of MGC-803 cells into nude mice illustrated the same effects of ZNF852 on the proliferation and self-renewal of gastric cancer cells. Similar effects of ANF852 were also seen in gastric cancer cell line SNU-1. Interestingly, ZNF852 deficiency caused downregulation of epidermal growth factor receptor (EGFR) on gastric cancer cells.In summary, this study uncovers the positive regulatory role of ZNF852 in gastric cancer growth and maintenance. ZNF852 could be a potential therapeutic target for inhibiting gastric cancer initiation or progression.

The role of zinc finger proteins in malignant tumors

“…Besides, ZNFs can promote cell proliferation, migration, invasion, and accelerate tumor progression. For instance, the high expression of ZFX, 51 ZNF687, 52 and ZNF852 66 in gastric cancer can enhance the cell stemness. However, some ZNFs also play a tumor suppressor role, such as ZNF746, 75 ZNF277, 77 and ZNF545 78,79 in colorectal cancer, ZNF382 42 and ZNF774 43 in liver cancer.…”

“…65 Furthermore, ZNF852 is upregulated in gastric cancer tissues, promoting the expression of stemness genes such as SOX2, OCT4, Nanog, and consequently reducing drug sensitivity. 66 However, ZNFs are also shown to function as tumor suppressor in gastric cancer. ZNF479 reduces the expression of glycolytic proteins in vitro and in vivo by downregulating βcatenin/c-Myc pathway and effectively blocks gastric cancer cell proliferation and glycolytic.…”

“…Besides, ZNF139 can improve the expression of the matrix metalloproteinases MMP‐2, MMP‐9, and ICAM‐1, and TIMP‐1 65 . Furthermore, ZNF852 is up‐regulated in gastric cancer tissues, promoting the expression of stemness genes such as SOX2, OCT4, Nanog, and consequently reducing drug sensitivity 66 …”

Zinc Finger Proteins in the War on Gastric Cancer: Molecular Mechanism and Clinical Potential

“…In GC, a large number of highly expressed C2H2-type ZFPs promote cell proliferation, specifically ZNF852, ZNF521, ZNF460, ZNF280B, ZNF143, zinc finger protein X-linked (ZFX), DAZ-interacting zinc finger protein 1 (DZIP1), E3 ubiquitin ligase ring finger protein 114 (RNF114) and pleomorphic adenoma gene like-2 (PLAGL2). Ke et al found that the proliferation of GC cells could be suppressed when using a CRISPR/CAS803 system to knock out ZNF852 due to the downregulated epidermal growth factor receptor (EGFR) expression by ZNF852 deficiency [33]. A colony formation assay indicated that ZNF521 is substantially expressed in GC cells.…”

“…ZFP64 directly binds to the Galectin-1 (Gal-1) promoter to further enhance Gal-1 transcription and induce an embryonic cell-like phenotype in GC [53]. Moreover, when the ZNF852 is knocked down using the CRISPR/cas9 system in GC, its ability to reproduce is inhibited, along with the decreased expression of Nanog, SRY-box 2 (Sox2) and Oct4, meaning that ZNF852 preserves the self-renewal and tumor stem cell properties of GC [33]. However, it is not clear whether ZNF852 directly enhances the transcription of Nanog, Sox2 and Oct4, or whether Sox2 and Oct4 upregulate ZNF852 in the line with positive feedback.…”