Integration of bulk and single-cell RNA sequencing analyses elucidates the role of NUPR1 in tumour microenvironment and cancer development

Nuclear protein 1 (NUPR1), a multifunctional stress-inducible transcription factor, has emerged as a potential target for cancer treatment. However, a comprehensive exploration of NUPR1 across the pan-cancer landscape is still lacking. In this study, we utilized multi-omics data from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases to assess the expression, prognostic significance, genomic features, and immunological characteristics of NUPR1 in 33 cancer types. Significant dysregulation of NUPR1 was observed in multiple cancers, where its expression also demonstrated prognostic relevance in several cancer types. Mechanistically, NUPR1 was found to correlate with genomic instability, DNA methylation, tumor-infiltrating immune cells, DNA repair, and apoptosis across various cancers. To investigate the role of NUPR1 in the tumor microenvironment (TME), we analyzed single-cell RNA sequencing (scRNA-seq) data, revealing that NUPR1 was predominantly expressed in epithelial cells and macrophages, but not in lymphoid cells, dendritic cells, or mast cells across six cancer types. In BRCA, NUPR1 expression was associated with epithelial cell stemness, and high NUPR1 expression in epithelial cells and macrophages correlated with poorer prognosis. Furthermore, NUPR1 was identified as a potential biomarker for drug sensitivity and as a risk factor in BRCA. Inactivation of NUPR1 by ZZW-115 in BRCA cells resulted in anticancer and radiosensitizing effects, including suppressed migration, proliferation, invasion and mammosphere formation, promotion of macrophage M1 polarization and inhibition of M2 polarization, as well as enhanced irradiation-induced apoptosis, DNA damage and reactive oxygen species (ROS) production.