Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

Mak, Kylie Hin-Man; Lam, Yuk Man; Ng, Ray Kit

doi:10.1038/s41598-020-79601-7

Cited by 12 publications

(14 citation statements)

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“…However, in order to exclude the in uence of accidental factors, we continue to rigorously conduct univariate and multivariate analysis to con rm that KDM4B can be used as an independent risk factor for poor prognosis in UCEC patients(Table S1and Table S2). A large number of previous studies have demonstrated that KDM4B contributes to the progression of various malignancies such as gastric, prostate and colorectal cancers, and is strongly associated with poor prognosis, which is highly consistent with our study (17)(18)(19). In summary, it is not di cult to nd that KDM4B can act as a new oncogene in UCEC leading to poor prognosis of patients, but the possible mechanism of its oncogenesis needs to be further explored.…”

Section: Discussionsupporting

confidence: 91%

Large-Scale Analysis and Clinical Samples Reveals the Specific Clinical and Immune Features of KDM4B in UCEC

Zhang

Liu

Hou

et al. 2021

Preprint

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Background: Uterine Corpus Endometrial Carcinoma (UCEC) ranks fourth among female cancers in the world. Frustratingly, the 5-year survival rates for advanced patients are only 17%. KDM4B is overexpressed or dysregulated in a variety of cancers and could be associated with tumor progression and poor prognosis. Therefore, we performed bioinformatics analysis and in vitro assays to assess the role of KDM4B in UCEC. In addition, its relevance to immune cells in the tumor microenvironment was explored.Methods: The mRNA level and protein level of KDM4B in UCEC was evaluated using the TCGA, HPA and GEO database. Immunohistochemistry and western blotting were used to verify the protein expression level of KDM4B in two batches of clinical samples. Kaplan-Meier curves, Univariate and multivariate analysis were used to assess the correlation between KDM4B expression and prognosis. GO and KEGG were used to predict the function and mechanism of KDM4B, and four immunity related database were used to explore their relevance to the tumor immune microenvironment.Results: Firstly, the present study showed that KDM4B was significantly overexpressed in UCEC from several databases at the mRNA and protein levels, respectively. Immunohistochemistry and western blotting confirmed the abnormally overexpression of KDM4B. In addition, upregulation of KDM4B was associated with different clinicopathological prognostic factors. Secondly, overexpression of KDM4B was also associated with shorter OS and PFS. Univariate and multivariate analyses confirmed that KDM4B was an independent prognostic factor for poor prognosis. Then, GO and KEGG analysis revealed that KDM4B is enriched in biological processes and cellular signaling pathways closely related to immunity. Finally, KDM4B expression was closely associated with immune cell infiltration and immune checkpoints and it may be a new immune-related potential oncogene in UCEC.Conclusions: KDM4B may be a new potential oncogene for UCEC patients. It is of clinical significance that KDM4B may not only be used to assess the clinical prognosis of UCEC patients but may also be a target for immunotherapy or gene targeted therapy.

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Section: Discussionsupporting

confidence: 91%

Large-Scale Analysis and Clinical Samples Reveals the Specific Clinical and Immune Features of KDM4B in UCEC

Zhang

Liu

Hou

et al. 2021

Preprint

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“…KDM4B is critical for the maintenance of embryonic stem cells. KDM4B not only exerts histone demethylation ability to promote stem cell proliferation by interacting with Nanog at specific locations ( Das et al, 2014 ), but also ensures the continuous feeding ability of trophoblast cells ( Mak et al, 2021 ). Overexpression of KDM4B improves the survival rate of embryos in vitro ( Antony et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…This finding suggests that the presence of KDM4-related proteins in ESCs may inhibit cell differentiation and promote cell proliferation. Recent studies have demonstrated that KDM4B regulates and maintains gene transcription in the form of the KDM4B-TFAP2C-LSD1 complex in human trophoblast stem cells, thus protecting the normal development of trophoblast cells ( Mak et al, 2021 ).…”

Section: The Roles Of Kdm4b In Normal Developmentmentioning

confidence: 99%

“…In this review, we mainly focus on the KDM4B protein of the KDM4 family. KDM4B mainly turns on the expression of genes through histone demethylation, which can regulate stem cells self-renewal and differentiation ( Mak et al, 2021 ) and the development of a variety of organs ( Guo et al, 2011 ; Jun et al, 2011 ; Uribe et al, 2015 ). At present, KDM4B has been proved to induce the differentiation of mesenchymal stem cells, which has significant physiological significance for sexual organ formation and development ( Kawazu et al, 2011 ), bone formation ( Lee et al, 2016 ), liver development ( Guo et al, 2011 ), and invagination of inner ear ( Uribe et al, 2015 ) ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

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The Diverse Roles of Histone Demethylase KDM4B in Normal and Cancer Development and Progression

Wang

Cai

Zhao

et al. 2022

Front. Cell Dev. Biol.

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Histone methylation status is an important process associated with cell growth, survival, differentiation and gene expression in human diseases. As a member of the KDM4 family, KDM4B specifically targets H1.4K26, H3K9, H3K36, and H4K20, which affects both histone methylation and gene expression. Therefore, KDM4B is often regarded as a key intermediate protein in cellular pathways that plays an important role in growth and development as well as organ differentiation. However, KDM4B is broadly defined as an oncoprotein that plays key roles in processes related to tumorigenesis, including cell proliferation, cell survival, metastasis and so on. In this review, we discuss the diverse roles of KDM4B in contributing to cancer progression and normal developmental processes. Furthermore, we focus on recent studies highlighting the oncogenic functions of KDM4B in various kinds of cancers, which may be a novel therapeutic target for cancer treatment. We also provide a relatively complete report of the progress of research related to KDM4B inhibitors and discuss their potential as therapeutic agents for overcoming cancer.

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“…KDM3A plays a pivotal role in regulating the expression of endoderm differentiation master genes [ 43 ], and in a regulatory circuit with hypoxia, HIF and MMP12, it is conserved and facilitates placental adaptations to environmental challenges [ 44 ]. KDM4B is required for maintaining stemness of trophoblastic stem cells by various protein interactors and epigenetic targets [ 45 ]. KDM5A is vital for normal zygotic genome activation and early embryo development [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Dysregulation of Trophoblastic Gene Expression in Gestational Trophoblastic Disease

et al. 2021

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Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation and transcriptome data to reveal the epigenetic basis of disease pathways that may lead to benign or malignant GTDs. RNA-Seq, mRNA microarray, and Human Methylation 450 BeadChip data from complete moles and choriocarcinoma cells were bioinformatically analyzed. Paraffin-embedded tissues from complete moles and control placentas were used for tissue microarray construction, DNMT3B immunostaining and immunoscoring. We found that DNA methylation increases with disease severity in GTDs. Differentially expressed genes are mainly upregulated in moles while predominantly downregulated in choriocarcinoma. DNA methylation principally influences the gene expression of villous trophoblast differentiation-related or predominantly placenta-expressed genes in moles and choriocarcinoma cells. Affected genes in these subsets shared focal adhesion and actin cytoskeleton pathways in moles and choriocarcinoma. In moles, cell cycle and differentiation regulatory pathways, essential for trophoblast/placental development, were enriched. In choriocarcinoma cells, hormone biosynthetic, extracellular matrix-related, hypoxic gene regulatory, and differentiation-related signaling pathways were enriched. In moles, we found slight upregulation of DNMT3B protein, a developmentally important de novo DNA methylase, which is strongly overexpressed in choriocarcinoma cells that may partly be responsible for the large DNA methylation differences. Our findings provide new insights into the shared and disparate molecular pathways of disease in GTDs and may help in designing new diagnostic and therapeutic tools.

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Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

Cited by 12 publications

References 57 publications

Large-Scale Analysis and Clinical Samples Reveals the Specific Clinical and Immune Features of KDM4B in UCEC

Large-Scale Analysis and Clinical Samples Reveals the Specific Clinical and Immune Features of KDM4B in UCEC

The Diverse Roles of Histone Demethylase KDM4B in Normal and Cancer Development and Progression

Epigenetic Dysregulation of Trophoblastic Gene Expression in Gestational Trophoblastic Disease

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