JMJD8 Is an M2 Macrophage Biomarker, and It Associates With DNA Damage Repair to Facilitate Stemness Maintenance, Chemoresistance, and Immunosuppression in Pan-Cancer

Abstract

BackgroundJMJD8 has recently been identified as a cancer-related gene, but current studies provide limited information. We aimed to clarify its roles and the potential mechanisms in pan-cancer.MethodsPan-cancer bulk sequencing data and online web tools were applied to analyze JMJD8’s correlations with prognosis, genome instability, cancer stemness, DNA repair, and immune infiltration. Moreover, single-cell datasets, SpatialDB database, and multiple fluorescence staining were used to validate the association between JMJD8 expression and M2 macrophages. Further, we utilized ROCplotter and cMap web tool to analyze the therapeutic responses and screened JMJD8-targeted compounds, respectively, and we used AlphaFold2 and Discovery Studio to conduct JMJD8 homology modeling and molecular docking.ResultsWe first noticed that JMJD8 was an oncogene in many cancer types. High JMJD8 was associated with lower genome stability. We then found that high JMJD8 correlated with high expression of mismatch repair genes, stemness, homologous repair gene signature in more than 9 cancers. ESTIMATE and cytokine analyses results presented JMJD8’s association with immunosuppression. Also, immune checkpoint CD276 was positively relevant to JMJD8. Subsequently, we validated JMJD8 as the M2 macrophage marker and showed its connection with other immunosuppressive cells and CD8+ T-cell depression. Finally, potential JMJD8-targeted drugs were screened out and docked to JMJD8 protein.ConclusionWe found that JMJD8 was a novel oncogene, and it correlated with immunosuppression and DNA repair. JMJD8 was highly associated with immune checkpoint CD276 and was an M2 macrophage biomarker in many cancers. This study will reveal JMJD8’s roles in pan-cancer and its potential as a novel therapeutic target.

LncRNA RARA-AS1 could serve as a novel prognostic biomarker in pan-cancer and promote proliferation and migration in glioblastoma

“…Based on our research results, we have made some bold speculations, such as RARA-AS1-induced T cells follicular helper cells in GBM to participate in immune responses, and RARA-AS1-promoted Macrophages M2 infiltration in LUAD to participate in immune responses. In previous studies, correlation analysis was also applied, and the gene JMJD8 was found to be highly correlated with M2 macrophages, confirming its potential as a therapeutic target 31 .…”

The prognostic and immunological role of MCM3 in pan-cancer and validation of prognosis in a clinical lower-grade glioma cohort

“…We extracted expression data for immune checkpoint components (inhibitory and stimulatory) and several PCD (pyroptosis, cuproptosis, anoikis, necroptosis, disulfdptosis and autophagy) markers and evaluated the association of MCM3 expression with these markers. The correlation of MCM3 with 5 MMR signatures and 44 RNA modification genes (m1A, m5C and m6A) in pan-cancer was analysed ( Liang et al, 2022 ). In addition, we obtained pan-cancer differentially methylated probe-based stemness index (DMPsi) from the study by Malta et al to determine the relationship between MCM3 expression and cancer stemness ( Malta et al, 2018 ).…”

Molecular genetic features and clinical manifestations in Chinese familial cerebral cavernous malformation: from a novel KRIT1/CCM1 mutation (c.1119dupT) to an overall view

“…It can still be predicted in the absence of homologous templates. As previously reported ( Liang et al, 2022 ), using the default parameters of Alphafold2 to predict the structure of KRIT1 wild-type and mutant proteins, the optimal model was selected and obtained the protein data bank (PDB) files of the three-dimensional structure of KRIT1 protein. Meanwhile, to visualize the mutant and wild-type KRIT1 protein structures, the predicted PDB files were imported into Swiss-PDB Viewer (Version 4.0.4) for protein structure drawing.…”