Expression, Prognostic Value, and Functional Mechanism of the KDM5 Family in Pancreatic Cancer

Abstract

Background: The histone lysine demethylase KDM5 family is an important epigenetic state-modifying enzyme family. Increasing evidence supports that epigenetic abnormalities in the KDM5 family are related to multiple cancers in humans. However, the role of the KDM5 family in pancreatic cancer is not clear, and related research is very scarce.Methods: R software, Kaplan–Meier Plotter, cBioPortal, TIMER, LinkedOmics, STRING, Metascape, TISIDB, and the GSCA Lite online tool were utilized for bioinformatics analysis.Results: KDM5A/B/C was significantly overexpressed in many kinds of tumor tissues, including pancreatic adenocarcinoma (PAAD), while the expression of KDM5D was significantly downregulated. The high expression of KDM5A/B/C was related to poor clinical features, such as worse treatment efficacy, higher tumor grade, and more advanced clinical stage. Patients with a family history of breast cancer and melanoma, history of drinking or history chronic pancreatitis were more likely to have KDM5A/B/C gene abnormalities, which were related to a variety of adverse clinical features. The results of gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway analyses of the KDM5 family and its 800 co-expressed genes showed that many gene terms related to cell proliferation, migration and many carcinogenic pathways. Notably, we found that the expression level of KDM5A/B/C was positively correlated with the expression of multiple key driver genes such as KRAS, BRCA1, and BRCA2 etc. In addition, PPI network analysis showed KDM5 family proteins have strong interactions with histone deacetylase family 1 (HDAC1), which could modify the lysines of histone H3, and co-act on many pathways, including the “longevity-regulating pathway” and “Notch signaling pathway”. Moreover, the upregulation of KDM5A/B/C expression was associated with an increase in the infiltration of B cells, CD8+ T cells and other infiltrating immune lymphocytes and the expression levels of immune molecules such as NT5E and CD274. Interestingly, the overexpression of KDM5A/C was also corelated with reduced sensitivity of pancreatic cancer cells to many kinds of pancreatic cancer-targeting or chemotherapeutic drugs, including axitinib and gemcitabine.Conclusion: KDM5 family members may be prognostic markers and new therapeutic targets for patients with pancreatic cancer.

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy

“…Interestingly, KDM2A expression in cancer-associated fibroblast promotes carcinogenesis and inhibition of KDM2A suppress the tumor growth via inhibiting PDL1 expression in breast cancer fibroblast cell lines [ 117 ]. Recent large data base analysis revealed that up-regulation of KDM5A/B/C expression was associated with infiltrating immune cells in pancreatic cancer [ 118 ]. Since the activity of KDM family members regulate tumor immunity, therapeutically targeting these proteins in combination with immune checkpoint inhibitors against pancreatic adenocarcinoma needs investigation.…”

The ctDNA-based postoperative molecular residual disease status in different subtypes of early-stage breast cancer

“…In order to understand the functional mechanism of the detected gene mutations in breast cancer with MRD-positive or MRD-negative, KEGG pathway enrichment analysis was performed based on the Metascape database as described previously ( 15 ). All somatic mutations involved in the 125 and 259 gene from 18 MRD-positive patients or 64-negative patients were included in KEGG enrichment analysis, respectively ( Figure 5 ).…”

Loss of Chromosome Y in Neuroblastoma Is Associated With High‐Risk Disease, 11q‐Deletion, and Telomere Maintenance

“…While the function of the two long noncoding RNA ASMTL-AS1 and LINC00685 is not fully elucidated, it is established that KDM5D (at Yq11.223) encodes a lysin-specific histone H3 demethylase. It has been shown that KDM5D is downregulated and/or associated with poor survival in different malignancies including colorectal cancer [47], lung cancer [48], pancreatic cancer [49], clear cell renal cell carcinoma [50], and gastric cancer [51]. Pathway analysis of autosomal genes with expression levels correlating to KDM5D in male NB tumors indicated epithelial-mesenchymal transition (EMT) and cell migration as top biological processes (Figure 5).…”