NOP2-regulated m5C Methylation of FKBP4 in Promoting Lung Adenocarcinoma Progression.
TL;DR
It is demonstrated that NOP2 promotes LUAD progression by regulating FKBP4 expression, potentially through m5C methylation, thereby highlighting the NOP2/FKBP4 axis as a potential therapeutic target.
Abstract
Background
Nucleolar protein 2 (NOP2), an RNA methyltransferase that mediates m5C modification, has been implicated in cancer progression; however, its specific role in lung adenocarcinoma (LUAD) remains unclear. This study investigated the functional significance of NOP2 and its regulation of FK506-binding protein 4 (FKBP4) in LUAD pathogenesis.
Materials And Methods
The human normal alveolar epithelial cell line HPAEpiC and the LUAD cell lines A549 and H1975 were utilized in this study. In vivo experiments were conducted using male Sprague-Dawley rats. The functional roles of NOP2 and FKBP4 were explored by transfecting LUAD cells with overexpression vectors or small interfering RNAs (siRNAs). Quantitative real-time PCR, western blotting, immunofluorescence, and immunohistochemical staining analyses were used to evaluate NOP2 and FKBP4 expression in cells and tissues. Cell viability and proliferation were assessed using Cell Counting Kit-8 assays and 5-ethynyl-2'-deoxyuridine (EdU) staining. Apoptosis was measured by flow cytometry and TUNEL staining. Transwell assays were conducted to determine cell migration and invasion. Co-immunoprecipitation and RNA pulldown assays were conducted to characterize the interaction between NOP2 and FKBP4.
Results
Analysis of data from The Cancer Genome Atlas (TCGA) database revealed that elevated expression of NOP2 and FKBP4 correlated with poor prognosis in patients with LUAD. Both NOP2 and FKBP4 were significantly upregulated in LUAD cell lines compared to normal controls. Knockdown of NOP2 could inhibit LUAD cell proliferation, migration, and invasion, and enhance apoptosis. In vivo experiments confirmed that NOP2 depletion inhibited tumor growth and enhanced apoptosis. Mechanistically, NOP2 could directly bind to FKBP4 and regulate its expression. Importantly, FKBP4 knockdown reversed the oncogenic effects of NOP2 expression, establishing FKBP4 as a critical downstream effector of NOP2 in LUAD.
Conclusion
Our study demonstrates that NOP2 promotes LUAD progression by regulating FKBP4 expression, potentially through m5C methylation, thereby highlighting the NOP2/FKBP4 axis as a potential therapeutic target. Overall, these findings provide new insights into the epigenetic mechanisms driving LUAD aggressiveness.