Nop2/Sun domain family member 5 contributes to tumorigenic properties in prostate cancer by engaging the PI3K-AKT pathway and tumor-associated macrophages

Purpose: Nop2/Sun domain family member 5 (NSUN5), a member of the m5C methylation family, plays a critical role in various biological processes by influencing RNA stability and regulating gene expression. The main purpose of this study was to determine the specific role of NSUN5 in prostate Cancer (PCa) progression.

Methods: TCGA-PRAD database was used to analyze the differential expression of NSUN5 between PCa and normal tissues, as well as its association with survival outcomes, signaling pathways, and immune infiltration. Subsequently, immunohistochemistry was performed to evaluate NSUN5 expression in PCa tissues. Functional assays, including gain- and loss-of-function experiments, were conducted to explore the effects of NSUN5 on PCa cell proliferation, migration, and the expression of key proteins in relevant signaling pathways. Cell co-culture, in vivo experiments, and flow cytometry analysis were used to explore the effects of NSUN5 on macrophage polarization and the immune microenvironment of PCa.

Results: NSUN5 is significantly overexpressed in PCa tissues and is positively correlated with advanced disease stages and poor patient prognosis. Functionally, NSUN5 enhances in vitro proliferation and migration, as well as in vivo tumor growth, primarily through activation of the PI3K-AKT signaling pathway. Moreover, NSUN5 facilitates the polarization of macrophages into tumor-associated macrophages within PCa tissues, thereby contributing to immune evasion.

Conclusion: NSUN5 promotes PCa progression through the PI3K-AKT pathway and induces macrophage polarization toward a pro-tumor phenotype, promoting the formation of a suppressive tumor microenvironment.

NSUN5; PI3K-AKT; Prostate cancer; Therapeutic target; Tumor-associated macrophages.