ZNF528 as a novel driver of metastasis in lung cancer: insights from single-cell transcriptomics

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality due to frequent metastasis, despite therapeutic advances. This study aims to identify novel drivers of NSCLC metastasis to facilitate the development of prognostic biomarkers and therapeutic targets.

We analyzed single-cell RNA-seq data (GSE121907) to identify differentially expressed genes (DEGs) in epithelial cells from metastatic NSCLC. Functional enrichment was performed. Based on bioinformatic findings, we investigated the role of zinc finger protein 528 (ZNF528) through gain- and loss-of-function studies in NSCLC cell lines. Cellular proliferation, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays, respectively. Epithelial-mesenchymal transition (EMT) markers were analyzed by immunoblotting. A cell-derived xenograft (CDX) model was established to evaluate tumor growth and metastasis in vivo.

Single-cell analysis revealed an expanded epithelial compartment in metastatic samples. Among the DEGs identified in these epithelial cells, ZNF528 was significantly upregulated. Pathway analysis indicated enrichment of ZNF528-correlated genes in proliferation and invasion-related pathways (e.g., NF-κB, MAPK). Consistently, functional assays demonstrated that ZNF528 knockdown suppressed, while its overexpression enhanced, NSCLC cell proliferation, migration, invasion, and EMT in vitro. Moreover, ZNF528 overexpression promoted tumor growth and metastasis in mouse xenograft models.

ZNF528 acts as a novel promoter of NSCLC metastasis, representing a potential prognostic biomarker and therapeutic target.