Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Corujo, David; Buschbeck, Marcus

doi:10.3390/cancers10030059

Cited by 82 publications

(80 citation statements)

References 230 publications

(257 reference statements)

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“…The altered expression of H2As has been found in cancers and resulted in different consequences. Whereas the H2AFX and H2AFY are considered as tumor suppressors, H2AFZ exhibits an oncogenic function [43]. Here, we further show that H2AFJ likely serves as a driver in promoting TMZ resistance and may be associated with the mesenchymal differentiation in GBM.…”

Section: Discussionsupporting

confidence: 55%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

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Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.

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Section: Discussionsupporting

confidence: 55%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

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“…H2A.X was considered as exerting tumour suppressive roles and is considered as a biomarker for drug response [21]. In triple-negative breast cancer and melanoma, S139 phosphorylation of H2A.X was occurred and was correlated with poor prognosis [22][23][24].…”

Section: Discussionmentioning

confidence: 99%

KRas-ERK signalling promotes the onset and maintenance of uveal melanoma through regulating JMJD6-mediated H2A.X phosphorylation at tyrosine 39

Peng

Zou

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Since DNA damage is a first incident occurred during a tumour attack, it is rational that histone H2A.X phosphorylation on tyrosine 39 (H2A.X Y39ph) may act as a tumour-relevant factor. This study was aimed to test the authenticity of the hypothesis. Uveal melanoma MP65 cells were transfected for expression of KRas mutated. H2A.X phosphorylation and ERK1/2 was measured, and transwell experiment was performed to examine the consequents of H2A.X Y39ph on MP65 cells developing and migration. Regulatory relationship between H2A.X Y39ph and ERK1/2 downstream genes were measured. Moreover, whether JMJD6 and MDM2 are involved in H2A.X phosphorylation was studied. Mutation of Ras activated ERK1/ 2 signalling and inhibited H2A.X phosphorylation at Y39. Silence of H2A.X Y39ph contributed to the regulation of MP65 cells growth, migration and transcription of ERK1/2 downstream genes, including CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16. The repressed H2A.X phosphorylation through Ras-ERK1/2 signalling might be through MDM2-mediated JMJD6 degradation. Our study suggested that Ras-ERK1/2 signalling inhibited H2A.X phosphorylation at Y39, which led to the uncontrolled developing and migration of uveal melanoma cells. In addition, H2A.X phosphorylation was mediated possibly through JMJD6 which could be degraded by MDM2.

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“…The expression ratio of MacroH2A1.1 and MacroH2A1.2, the two isoforms of H2AFY, may be of great signi cance. MacroH2A1.1 acts as a tumour suppressor by inhibiting cell proliferation, migration, and invasion, while the function of MacroH2A1.2 is largely dependent on the type of cancer (18,32). In differentiated and proliferating cells, MacroH2A1.1 and MacroH2A1.2 have obvious expression differences: MacroH2A1.1 is primarily found in differentiated cells, while MacroH2A1.2 is mainly found in proliferating cells (33,34).…”

Section: Discussionmentioning

confidence: 99%

The diagnostic and prognostic value of H2AFY in hepatocellular carcinoma

Ding²,

Zeng

2020

Preprint

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Background: The potential correlation between H2AFY (also known as MacroH2A1) and the clinical characteristics of hepatocellular carcinoma (HCC) patients was analysed through gene expression profiles and clinical data in The Cancer Genome Atlas (TCGA) database, and the diagnostic and prognostic value of H2AFY in HCC was discussed. Methods: The gene expression data of HCC and the corresponding clinical characteristics of HCC patients were downloaded from the TCGA database. The differences in H2AFY in normal liver tissues and HCC were analysed. The relationship between H2AFY and clinical characteristics was analysed by Wilcoxon signed-rank test, logistic regression and Kruskal-Wallis test. The Kaplan-Meier method and the Cox regression method were used to analyse the relationship between overall survival and clinical characteristics of the patients. An ROC curve was used to predict the diagnostic value of H2AFY in HCC. Gene set enrichment analysis (GSEA) was used to analyse the pathway enrichment of H2AFY. Result: Compared with normal liver tissues, H2AFY was significantly highly expressed in HCC. H2AFY was positively correlated with the age, clinical stage, G stage (grade) and T stage (tumor stage) of liver cancer patients. Higher H2AFY expression predicted a poor prognosis in HCC patients. Cox regression analysis suggested that H2AFY was an independent risk factor for the prognosis of HCC patients. The ROC curve suggested that H2AFY had certain diagnostic value in HCC. GSEA suggested that H2AFY was correlated with lipid metabolism and a variety of tumour pathways. Conclusion: Our study showed that H2AFY was significantly overexpressed in HCC. H2AFY may be a potential diagnostic and prognostic marker for HCC, and high expression of H2AFY predicts a poor prognosis in patients with HCC.

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Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cited by 82 publications

References 230 publications

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

KRas-ERK signalling promotes the onset and maintenance of uveal melanoma through regulating JMJD6-mediated H2A.X phosphorylation at tyrosine 39

The diagnostic and prognostic value of H2AFY in hepatocellular carcinoma

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