Bioinformatics analysis of DNMT1 expression and its role in head and neck squamous cell carcinoma prognosis

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of malignancy in the world. DNA cytosine-5-methyltransferase 1 (DNMT1) play key roles in carcinogenesis and regulation of the immune micro-environment, but the gene expression and the role of DNMT1 in HNSCC is unknown. In this study, we utilized online tools and databases for pan-cancer and HNSCC analysis of DNMT1 expression and its association with clinical cancer characteristics. We also identified genes that positively and negatively correlated with DNMT1 expression and identified eight hub genes based on protein-protein interaction (PPI) network analysis. Enrichment analyses were performed to explore the biological functions related with of DNMT1. The Tumor Immune Estimation Resource (TIMER) database was performed to explore the relationship between DNMT1 expression and immune-cell infiltration. We demonstrated that DNMT1 gene expression was upregulated in HNSCC and associated with poor prognosis. Based on analysis of the eight hub genes, we determined that DNMT1 may be involved in cell cycle, proliferation and metabolic related pathways. We also found that significant difference of B cells infiltration based on TP 53 mutation. These findings suggest that DNMT1 related epigenetic alterations have close relationship with HNSCC progression, and DNMT1 could be a novel diagnostic biomarker and a promising therapeutic target for HNSCC.

Figure 1

High DNMT1 expression was observed in head and neck cancers and in pan-cancers (A) High DNMT1 expression was found in several types of cancers. (B) The DNMT1 transcript level was significantly higher in HNSCC tissue than in non-tumor tissue. (C) DNMT1 protein expression was higher in HNSCC tumor tissue than in non-tumor tissue.

Figure 2

Relationships between DNMT1 expression and clinical characteristics and prognosis were analyzed. (A–G) DNMT1 expression correlated with gender, age, race, tumor grade, and HPV infectious status, but not with lymphatic invasion or tumor stage. (H, I) OS and RFS analyses demonstrated that patients with high DNMT1 expression had poor clinical prognosis.

Figure 3

Distribution of DNMT1 mutations and co-expressed genes. (A) In HNSCC, the somatic mutation rate was 1.6%. (B) CLSPN, UHRF1, BRCA1, ATAD5, TIMELESS, CIT, KIF4B, and DTL genes were co-expressed with DNMT1.

Figure 4

The relationship between DNMT1 expression and immune cell infiltration and clinical prognosis of HNSCC. (A) DNMT1 gene expression positively correlated with tumor purity and infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells in HNSCC. (B) DNMT1 expression did not correlate with tumor purity and macrophage infiltration in the HPV-positive HNSCC group. Infiltration of B cells, CD8 + T cells, CD4 + T cells, neutrophils, and dendritic cells correlated weakly with DNMT1 expression in the HPV-positive HNSCC subgroup. (C) DNMT1 expression positively correlated with tumor purity and infiltration of CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells, but not with infiltration of B cells, in the HPV-negative HNSCC subgroup. (D) TP53 mutation with immune cells infiltration in HNSC.

Figure 5

Distribution of genes that associated with DNMT1 expression. (A) The volcano map shows the genes that positively and negatively correlated with DNMT1 expression. (B) The heat-map shows the top 10 genes that positively correlated and negatively with DNMT1 expression.

Figure 6

GO enrichment and KEGG pathways analyses of the top 100 genes that positively correlated with DNMT1 expression. (A) GO BP enrichment analysis of DNMT1-associated genes. (B) GO CC enrichment analysis of DNMT1-associated genes. (C) Go MF enrichment analysis of DNMT1-associated genes. (D) KEGG analysis of DNMT1-associated genes.

Figure 7

The PPI network was based on the top 100 DNMT1-related genes. (A) The distribution of the top 100 DNMT1-related genes is shown, and the red-colored nodes represent the log (FC) values of the Z-scores of the proteins that interact with the designated protein. (B) 8 hub genes were identified with Cytoscape software. The red-color represents genes that positively correlated with DNMT1 expression. (c) Correlations between expression of hub genes and DNMT1 expression.