Multiple Comprehensive Analyses Identify Lysine Demethylase KDM as a Potential Therapeutic Target for Pancreatic Cancer

Abstract

Pancreatic cancer (PC) is a challenging and heterogeneous disease with a high mortality rate. Despite advancements in treatment, the prognosis for PC patients remains poor, with a high chance of disease recurrence. Biomarkers are crucial for diagnosing cancer, predicting patient prognosis and selecting treatments. However, the current lack of effective biomarkers for PC could contribute to the insufficiency of existing treatments. These findings underscore the urgent need to develop novel strategies to fight this disease. This study utilized multiple comprehensive bioinformatic analyses to identify potential therapeutic target genes in PC, focusing on histone lysine demethylases (KDMs). We found that high expression levels of KDM family genes, particularly KDM1A, KDM5A and KDM5B, were associated with improved overall survival in the cohort. Furthermore, the infiltration of various immune cells, including B cells, neutrophils, CD8⁺ T cells, dendritic cells, and macrophages, was positively correlated with KDM1A, KDM5A, and KDM5B expression. Moreover, MetaCore pathway analysis revealed interesting connections between KDM1A and the cell cycle and proliferation, between KDM5A and DNA damage and double-strand break repair through homologous recombination, and between KDM5B and WNT/β-catenin signaling. These findings suggest that KDM1A, KDM5A and KDM5B may serve as promising biomarkers and therapeutic targets for PC, a disease of high importance due to its aggressive nature and urgent need for novel biomarkers to improve diagnosis and treatment.

Figure 1

The bioinformatics analysis flowchart depicts the processing of publicly available data from TCGA and GTEx databases.

Figure 2

The expression levels of KDM family proteins in pancreatic cancer (PC). KDM family mRNA expression analysis in PCs from the GEPIA2 database. Box plot (GEPIA2): normal tissue, gray; tumor tissue, red. *, p<0.01.

Figure 3

The prognostic value of the mRNA levels of the KDM family in patients with pancreatic cancer (PC) was determined via Kaplan‒Meier plotter analysis. (A) The hazard ratio (HR) indicates the prognostic value for PC patients. The log [rank p] test was used to determine the level of prognostic significance, with a value of p<0.05 considered significant. High expression of KDM1A/5A/5B was significantly associated with poor prognosis, indicating poorer outcomes. Conversely, the HRs of KDM2B/5D/6B were significantly lower, suggesting better prognostic outcomes in patients with pancreatic cancer. (B) Immunohistochemical patterns of KDM1A, KDM5A, and KDM5B expression in normal and tumor tissues from patients with PC.

Figure 4

Correlation analysis was performed to assess the relationships between differentially expressed KDM family genes and immune cell infiltration via the TIMER database. The figure illustrates the associations of KDM1A, KDM5A, and KDM5B gene expression with tumor purity and markers of tumor-infiltrating immune cells, including B cells, CD8⁺ T cells, CD4⁺ T cells, macrophages, neutrophils, and dendritic cells. Spearman correlations were used to assess the relationships between these KDM genes and the mentioned immune cells, with statistical significance set at p<0.05.

Figure 5

MetaCore pathway analysis of the coexpression gene network involving KDM1A in pancreatic cancer. We extracted the top 1000 genes coexpressed with KDM1A from the TCGA database. We conducted a pathway analysis and generated a pathway list ordered by the -log p value. The "Ephrin receptors pathway" ranked highest in the biological process category. The figure illustrates interactions between genes and proteins, with symbols representing proteins and arrows depicting protein interactions (green for activation, red for inhibition).

Figure 6

Expression of the KDM5A signaling pathway in pancreatic cancer (MetaCore). We used the MetaCore platform to analyze genes coexpressed with KDM5A from the associated TCGA database. Our analysis revealed that "DNA damage" was the most common biological process.

Figure 7

MetaCore enrichment pathway analysis of genes coexpressed with KDM5B in pancreatic cancer. We used the MetaCore platform to analyze genes coexpressed with KDM5B from the associated TCGA database. Our analysis revealed that "WNT/β-catenin signaling" ranked highest in the biological process analysis.