The role of YTH domain containing 2 in epigenetic modification and immune infiltration of pan‐cancer

Background: Serpin peptidase inhibitor clade H, member 1 (SERPINH1) is a gene encoding a member of the serpin superfamily of serine proteinase inhibitors. The upregulated of SERPINH1 was associated with poor prognosis in breast cancer, stomach adenocarcinoma, and esophageal carcinoma. However, the role of SERPINH1 in pan-cancer is largely unexplored.Methods: SERPINH1 expression and the correlation with prognosis in human pan-cancer were analyzed by the Cancer Genome Atlas and the Genotype-Tissue Expression dataset. Pearson correlation analysis was applied to evaluate the role of SERPINH1 expression in tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), DNA methyltransferase, and common immunoregulators. Spearman’s correlation test was used to analysis SERPINH1 expression in tumor immune infiltration and infiltrating immune cells via the Tumor Immune Evaluation Resource database. Furtherly, immunohistochemistry staining of SERPINH1 was acquired from the Human Protein Atlas database for validation.Results: SERPINH1 was abnormally expressed in fourteen cancers. The high expression of SERPINH1 significantly reduced the overall survival (OS), disease-specific survival, and progression free interval in eleven cancers. Moreover, SERPINH1 expression was correlated with MMR, MSI, TMB, and DNA methylation in multiple types of cancer. Also, SERPINH1 expression showed strong association with immunoregulators and immune checkpoint markers in testicular germ cell tumors, brain lower grade glioma (LGG), pheochromocytoma and paraganglioma. In addition, SERPINH1 expression was related to immune cell infiltration in multiple cancers, particularly in breast invasive carcinoma, LGG, and liver hepatocellular carcinoma. The result of immunohistochemistry verification shown that SERPINH1 staining was higher in tumor samples than in normal tissue in colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma and cervical squamous cell carcinoma, which was consistent with the result of OS.Conclusion: Overall, these results indicate that SERPINH1 may serve as an important prognostic biomarker and correlate with tumor immunity in human pan-cancer.

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The Role of M6A-related CBLL1 in the Prognosis and Immune Infiltration of Pan-cancer

10.21203/rs.3.rs-40873/v1 ◽

2020 ◽

Author(s):

Qiang Guo ◽

Dan Li ◽

Yan-Mei Ji ◽

Jialong Guo

Keyword(s):

Mrna Expression ◽

Immune Cells ◽

Gene Set Enrichment Analysis ◽

Expression Level ◽

Cycle Phase ◽

Immune Infiltration ◽

The Relationship ◽

Pan Cancer ◽

Ucsc Database

Abstract Background The modification of N6-methyladenosine (m6A) plays an important role in physiology and disease progression. The relationship between the role of m6a-related gene CBLL1 in pan-carcinoma and tumor immune infiltrates has remained unknown. Methods To explore the expression level of CBLL1 methylation in pan-cancer in SMART database, and download mRNA expression, mutation and clinical data in UCSC database, to analyze the expression level of CBLL1, and the relationship between CBLL1 expression and clinicopathological features, prognosis, mutation and immune microenvironment in pan-cancer. CIBERSORT was used to analyze the relationship between the expression of CBLL1 and the infiltration of pan-carcinoma immune cells. The mRNA expression data of UCSC database were used to analyze the correlation between CBLL1 expression and pan-cancer immunomodulations, checkpoints and receptor molecules. Gene Set enrichment analysis (GSEA) revealed the possible mechanism of CBLL1 in the regulation of pan-cancer progression. Results The levels of CBLL1 methylation and mRNA expression in pan-cancer tissues were abnormal. The level of CBLL1 is related to the age, race, clinical stage and treatment effect of patients with pan-carcinoma and associated with the prognosis of patients with KIRC, LUSC, THCA, THYM, MESO, PRAD, STAD, and UVM. Univariate COX regression analysis showed that expression of CBLL1 was a risk factor for poor prognosis in patients with KICH, KIRC, LAML, THYM, KIRC, PCPG, OV, PRAD, STAD, GBM and UVM.The expression level of CBLL1 was correlated with BLCA, BRCA, COAD, LAML, LGG, LUAD, LUSC, SARC, STAD, THCA, THYM and UVM tumor mutational burden (TMB), and with ACC, BRCA, CESC, COAD, DLBC, HNSC, PRAD, READ, SARC, STAD, TGCT, THCA and UCEC microsatellite instability (MSI). The expression level of CBLL1 was correlated with pan-cancer stromal cells and immune cells. The expression of CBLL1 is related to pan-cancer immunomodulators, checkpoints and receptor molecules. GSEA found that CBLL1 may participate in the progression of pan-cancer through B cell receptor singaling pathway, mRNA binding, immunoglobulin receptor binding, Positive Regulation of cell cycle phase transition and other mechanisms. Conclusions CBLL1 is abnormally expressed in patients with pan-carcinoma, which is expected to be a biomarker for prognosis, mutation and immune infiltration in patients with pan-carcinoma.

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An Integrative Pan-Cancer Analysis of PBK in Human Tumors

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.755911 ◽

2021 ◽

Vol 8 ◽

Author(s):

Huantao Wen ◽

Zitao Chen ◽

Min Li ◽

Qiongzhen Huang ◽

Yuhao Deng ◽

...

Keyword(s):

T Cells ◽

Poor Prognosis ◽

Mitogen Activated Protein Kinase ◽

High Expression ◽

Immune Checkpoints ◽

Multiple Tumor ◽

Immune Infiltration ◽

Cancer Types ◽

Pan Cancer

Background: PDZ binding kinase (PBK) is a serine/threonine kinase, which belongs to the mitogen-activated protein kinase kinase (MAPKK) family. It has been shown to be a critical gene in the regulation of mitosis and tumorigenesis, but the role of PBK in various cancers remains unclear. In this study, we systematically explored the prognostic and predictive value of PBK expression in 33 cancer types.Methods: Public databases including the cBioPortal database, GDSC database, GTEx database, CCLE database, and TCGA database were used to detect the PBK expression and its association with the prognosis, clinicopathologic stage, TMB, MSI, immune microenvironment, immune checkpoints, immune cell infiltration, enrichment pathways, and IC50 across pan-cancer. The statistical analyses and visualization were conducted using R software.Results: PBK expression is relatively high in most cancers compared to their normal counterparts, and this gene is barely expressed in normal tissues. High expression of PBK is significantly associated with poor prognosis and clinicopathologic stages I, II, and III in different cancers. Furthermore, PBK expression is strongly associated with TMB in 23 cancer types and associated with MSI in nine cancer types. Moreover, the correlation analysis of the microenvironment and immune cells indicated that PBK is negatively correlated with the immune infiltration levels but positively correlated with the infiltration levels of M0 and M1 macrophages, T cells CD4 memory activated, and T cells follicular helper. GSEA analysis revealed that the biological function or pathways relevant to the cell cycle and mitosis were frequently enriched at the level of high expression of PBK.Conclusion: These results revealed the oncogenic role of PBK, which is significantly upregulated in various cancers and indicated poor prognosis and immune infiltration in multiple cancers. It also suggested that PBK may serve as a biomarker in multiple tumor progress and patient survival.

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The Role of CBLL1 in the Prognosis and Immune Infiltration of Pan-Cancer

10.21203/rs.3.rs-91598/v1 ◽

2020 ◽

Author(s):

Qiang Guo ◽

Dan Li ◽

Yanmei Ji ◽

Jialong Guo

Keyword(s):

Mrna Expression ◽

Immune Cells ◽

Cox Regression ◽

Expression Level ◽

Cox Regression Analysis ◽

Immune Infiltration ◽

The Relationship ◽

Pan Cancer ◽

Ucsc Database

Abstract ObjectiveThis study aims to explore the role of CBLL1 in pan-carcinoma and tumor immune infiltrates. MethodsDownload mRNA expression, mutation and clinical data in UCSC database, to analyze the relationship between CBLL1 expression and clinicopathological vlaue, and immune microenvironment in pan-cancer. CIBERSORT was used to analyze the relationship between CBLL1 expression and the infiltration of pan-carcinoma immune cells. The mRNA expression data of UCSC database were used to analyze the correlation between CBLL1 expression and pan-cancer immunomodulations, checkpoints and receptor molecules. ResultsThe levels of CBLL1 mRNA expression in pan-cancer tissues were abnormal. The level of CBLL1 is related to the age, race, clinical stage and treatment effect of patients with pan-carcinoma and associated with the prognosis of patients with KIRC, LUSC, THCA, THYM, MESO, PRAD, STAD, and UVM. Univariate COX regression analysis showed that expression of CBLL1 was a risk factor for poor prognosis in patients with KICH, KIRC, LAML, THYM, KIRC, PCPG, OV, PRAD, STAD, GBM and UVM. The expression level of CBLL1 was correlated with BLCA, BRCA, COAD, LAML, LGG, LUAD, LUSC, SARC, STAD, THCA, THYM and UVM tumor mutational burden, and with ACC, BRCA, CESC, COAD, DLBC, HNSC, PRAD, READ, SARC, STAD, TGCT, THCA and UCEC microsatellite instability. The expression level of CBLL1 was correlated with cancer stromal cells and immune cells. The expression of CBLL1 is related to pan-cancer immunomodulators, checkpoints and receptor molecules. ConclusionCBLL1 is abnormally expressed in patients with pan-carcinoma, which is expected to be a biomarker for prognosis, mutation and immune infiltration in patients with pan-carcinoma.

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Bioinformatics Analysis of ISLR in Pan-Cancer and its Correlation with Tumor Immunity

10.21203/rs.3.rs-970091/v1 ◽

2021 ◽

Author(s):

Cangyuan Zhang ◽

Ziyang Long ◽

Cheng Yan ◽

Mohamed Said Jalloh ◽

Yongkun Fang ◽

...

Keyword(s):

Tumor Immunity ◽

Bioinformatics Analysis ◽

Expression Patterns ◽

Clinical Prognosis ◽

Immune Infiltration ◽

Normal Tissues ◽

Genes Encoding ◽

Predictive Role ◽

Pan Cancer

Abstract Background The protein meflin encoded by ISLR contains a C2-type immunoglobulin (Ig)-like domain and five leucine-rich repeat (LRR) domains. ISLR is known to play a role in a small number of tumors, but its role in most tumors is unknown. The purpose of this study was to analyze the expression and prognosis of ISLR in pan-cancer, as well as its correlation with tumor immunity. Methods We used multiple databases and R software to conduct bioinformatics analysis to explore the predictive role of ISLR in pan-cancer, mainly involving expression patterns, prognosis, and immune infiltration. Results Compared with normal tissues, the expression of ISLR was significantly increased or decreased in most tumors. Moreover, the high expression of ISLR may cause the prognosis of some tumors to become better or worse. ISLR also affects immune infiltration in a variety of tumors, which affects the clinical prognosis. ISLR is also significantly related to TMB and MSI in pan-cancer and is related to genes encoding immune regulatory genes. ISLR also affects various cancer-and immune-related pathways. Conclusions ISLR is differentially expressed in tumors, may regulate TME, affect tumor prognosis, and is expected to become a prognostic biomarker.

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Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis

Cell Death and Disease ◽

10.1038/s41419-020-03381-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Takuma Nakatsuka ◽

Keisuke Tateishi ◽

Hiroyuki Kato ◽

Hiroaki Fujiwara ◽

Keisuke Yamamoto ◽

...

Keyword(s):

Dna Damage ◽

Epigenetic Modification ◽

Histone Methyltransferase ◽

Preventive Strategy ◽

Tumor Initiation ◽

Liver Transcriptome ◽

Genetic Abnormalities ◽

Responsive Element ◽

Induced Apoptosis

AbstractWhile the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9aΔHep and wild-type livers, more apoptotic hepatocytes were detected in the G9aΔHep liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9aΔHep liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.

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Prognostic and immunological role of Ras-related protein Rap1b in pan-cancer

Bioengineered ◽

10.1080/21655979.2021.1955559 ◽

2021 ◽

Vol 12 (1) ◽

pp. 4828-4840

Author(s):

Guoliang Cui ◽

Can Wang ◽

Zhenyan Lin ◽

Xiaoke Feng ◽

Muxin Wei ◽

...

Keyword(s):

Related Protein ◽

Pan Cancer

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DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors

Cerebral Cortex ◽

10.1093/cercor/bhaa337 ◽

2020 ◽

Author(s):

Jing Wei ◽

Jia Cheng ◽

Nicholas J Waddell ◽

Zi-Jun Wang ◽

Xiaodong Pang ◽

...

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

Epigenetic Modification ◽

Substantial Reduction ◽

Dna Methyltransferases ◽

Male Rats ◽

Neural Pathways ◽

Dnmt Inhibitors ◽

Synaptic Functions

Abstract Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.

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The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice

Biology ◽

10.3390/biology9050093 ◽

2020 ◽

Vol 9 (5) ◽

pp. 93 ◽

Cited By ~ 1

Author(s):

Seul Lee ◽

Dong-Cheol Woo ◽

Jeeheon Kang ◽

Moonjin Ra ◽

Ki Hyun Kim ◽

...

Keyword(s):

Liver Disease ◽

Epigenetic Modification ◽

Treatment Options ◽

Histone Methyltransferase ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Promising Therapeutic Target ◽

Alcoholic Fatty Liver Disease ◽

Potential Therapeutics

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.

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Pan-cancer analysis reveals tumor-associated macrophage communication in the tumor microenvironment

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00226-1 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Linbang Wang ◽

Tao He ◽

Jingkun Liu ◽

Jiaojiao Tai ◽

Bing Wang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Cell ◽

Hub Genes ◽

Tumor Associated Macrophage ◽

Molecular Features ◽

Receptor Interactions ◽

Tumor Types ◽

Pan Cancer

Abstract Background Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME). However, their contribution to the immunosuppressive status of the TME remains unclear. Methods We integrated single-cell sequencing and transcriptome data from different tumor types to uncover the molecular features of TAMs. In vitro experiments and prospective clinical tests confirmed the results of these analysis. Results We first detected intra- and inter-tumoral heterogeneities between TAM subpopulations and their functions, with CD86+ TAMs playing a crucial role in tumor progression. Next, we focused on the ligand-receptor interactions between TAMs and tumor cells in different TME phenotypes and discovered that aberrant expressions of six hub genes, including FLI1, are involved in this process. A TAM-tumor cell co-culture experiment proved that FLI1 was involved in tumor cell invasion, and FLI1 also showed a unique pattern in patients. Finally, TAMs were discovered to communicate with immune and stromal cells. Conclusion We determined the role of TAMs in the TME by focusing on their communication pattern with other TME components. Additionally, the screening of hub genes revealed potential therapeutic targets.

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