JMJD3 in the regulation of human diseases

Zhang, Xiangxian; Liu, Li; Yuan, Xia; Wei, Yuquan; Wei, Xiawei

doi:10.1007/s13238-019-0653-9

Cited by 78 publications

(55 citation statements)

References 144 publications

(180 reference statements)

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“…Compared with the well-defined oncogenic and pro-fibrotic functions of EZH2, JMJD3 is a double-edged sword with complex and somehow opposite functions in different context of disease, tissue and cell type. Accumulating evidence have shown that JMJD3 plays pro-inflammatory or anti-inflammatory in immune diseases, and carcinogenic or tumor suppressive roles in various types of cancer, which is associated with the histone demythylase activity-dependent epigenetic regulation and its noncanonical noncatalytic functions 23 , 65 . As JMJD3 stimulates a wide range of genes implicated in inflammation, immunity, development, senescence and carcinogenesis, its expression in normal conditions is usually in low level in the organization, just as its undetectable expression in the tested hepatic cell lines in this study, its activation is an important host response against environmental and cellular stress.…”

Section: Discussionmentioning

confidence: 99%

“…Removal of H3K27me2/3 methylation marks is specifically mediated by the JmjC domain-containing histone demethylases JMJD3 (KDM6B) and UTX (Ubiquitously transcribed Tetratricopeptide repeat on chromosome X) (KDM6A) 22 . JMJD3 is involved in cellular processes including differentiation, proliferation, senescence, and apoptosis, and thus is implicated in development and diseases 23 . JMJD3, UTX and EZH2 regulate hepatic plasticity inducing retro-differentiation and proliferation of hepatocytes 24 .…”

Section: Introductionmentioning

confidence: 99%

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Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis

et al. 2021

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Rationale: As the central hallmark of liver fibrosis, transdifferentiation of hepatic stellate cells (HSCs), the predominant contributor to fibrogenic hepatic myofibroblast responsible for extracellular matrix (ECM) deposition, is characterized with transcriptional and epigenetic remodeling. We aimed to characterize the roles of H3K27 methyltransferase EZH2 and demethylase JMJD3 and identify their effective pathways and novel target genes in HSCs activation and liver fibrosis. Methods: In primary HSCs, we analyzed effects of pharmacological inhibitions and genetic manipulations of EZH2 and JMJD3 on HSCs activation. In HSCs cell lines, we evaluated effects of EZH2 inhibition by DZNep on proliferation, cell cycling, senescence and apoptosis. In CCl 4 and BDL murine models of liver fibrosis, we assessed in vivo effects of DZNep administration and Ezh2 silencing. We profiled rat primary HSCs transcriptomes with RNA-seq, screened the pathways and genes associated with DZNep treatment, analyzed EZH2 and JMJD3 regulation towards target genes by ChIP-qPCR. Results: EZH2 inhibition by DZNep resulted in retarded growth, lowered cell viability, cell cycle arrest in S and G2 phases, strengthened senescence, and enhanced apoptosis of HSCs, decreased hepatic collagen deposition and rescued the elevated serum ALT and AST activities of diseased mice, and downregulated cellular and hepatic expressions of H3K27me3, EZH2, α-SMA and COL1A. Ezh2 silencing by RNA interference in vitro and in vivo showed similar effects. JMJD3 inhibition by GSK-J4 and overexpression of wild-type but not mutant Jmjd3 enhanced or repressed HSCs activation respectively. EZH2 inhibition by DZNep transcriptionally inactivated TGF-β1 pathway, cell cycle pathways and vast ECM components in primary HSCs. EZH2 inhibition decreased H3K27me3 recruitment at target genes encoding TGF-β1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, and increased their expressions, while Jmjd3 overexpression manifested alike effects. Conclusions: EZH2 and JMJD3 antagonistically modulate HSCs activation. The therapeutic effects of DZNep as epigenetic drug in liver fibrosis are associated with the regulation of EZH2 towards direct target genes encoding TGF-β1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, which are also regulated by JMJD3. Our present study provides new mechanistic insight into the epigenetic modulation of EZH2 and JMJD3 in HSCs biology and hepatic fibrogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis

et al. 2021

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“…Notably, based on intensive studies across a broad spectrum of tumors 40 , 41 , the functional roles of both KDM6A and KDM6B in tumorigenesis were found to be highly cell type-specific and pathologic context-dependent. For instance, KDM6B could promote TGF-β-induced epithelial-mesenchymal transition (EMT) through activating SNAI1 in breast cancer cells 42 , and instigate proliferative, metastatic, and self-renewal capacities of tumor cells in liver, ovarian, and skin cancers by modulating multiple signalings 24 , 43 , 44 .…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer

Zhang¹,

Ying²,

Li³

et al. 2020

Theranostics

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Tumor-initiating cells (TICs) maintain heterogeneity within tumors and seed metastases at distant sites, contributing to therapeutic resistance and disease recurrence. In colorectal cancer (CRC), strategy that effectively eradicates TICs and is of potential value for clinical use still remains in need. Methods : The anti-tumorigenic activity of a small-molecule inhibitor of KDM6 histone demethylases named GSK-J4 in CRC was evaluated by in vitro assays and in vivo imaging of xenografted tumors. Sphere formation, flow cytometry analysis of cell surface markers and intestinal organoid formation were performed to examine the impact of GSK-J4 on TIC properties. Transcriptome analysis and global profiling of H3K27ac, H3K27me3, and KDM6A levels by ChIP-seq were conducted to elucidate how KDM6 inhibition reshapes epigenetic landscape and thereby eliminating TICs. Results : GSK-J4 alleviated the malignant phenotypes of CRC cells in vitro and in vivo , sensitized them to chemotherapeutic treatment, and strongly repressed TIC properties and stemness-associated gene signatures in these cells. Mechanistically, KDM6 inhibition induced global enhancer reprogramming with a preferential impact on super-enhancer-associated genes, including some key genes that control stemness in CRC such as ID1 . Besides, expression of both Kdm6a and Kdm6b was more abundant in mouse intestinal crypt when compared with upper villus and inhibition of their activities blocked intestinal organoid formation. Finally, we unveiled the power of KDM6B in predicting both the overall survival outcome and recurrence of CRC patients. Conclusions : Our study provides a novel rational strategy to eradicate TICs through reshaping epigenetic landscape in CRC, which might also be beneficial for optimizing current therapeutics.

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“…JMJD3 is upregulated in different human cancers, such as gliomas, breast cancer, and lung cancer. 30 – 33 Thus, it is a novel target for the treatment of various types of cancer. Previous studies, including our work, showed that JMJD3 plays an important role in cell fate commitment, such as cellular reprograming into the pluripotent state.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma

Wang

Huang

You

et al. 2020

Sig Transduct Target Ther

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The adaptation of osteosarcoma cells to therapeutic pressure impedes the efficacy of chemotherapy for osteosarcoma. However, the characteristics and cellular organization of therapy-resistant cells in osteosarcoma tumors remain elusive. Here, we utilized single-cell transcriptomics to systematically map the cell-type-specific gene expression in a chemotherapy-resistant osteosarcoma tumor. Our data demonstrated the VEGFR2-JMJD3-abundant subsets as quiescent stem-like cells, thereby establishing the hierarchy of therapy-resistant actively cycling progenitor pools (JMJD3-abundant) in osteosarcoma. VEGFR2 inhibitor and JMJD3 inhibitor synergistically impeded osteosarcoma cell propagation and tumor growth. Although osteosarcoma cells are predisposed to apoptosis induced by the synergistic therapy through activation of the CHOP pro-apoptotic factor via the endoplasmic reticulum (ER) stress, the stem-like/progenitor cells exhibit an adaptive response, leading to their survival. Reduction in cellular glutathione levels in stem-like/progenitor cells caused by the treatment with a glutathione synthesis inhibitor increases ER stress-induced apoptosis. Importantly, the marked therapeutic improvement of synergistic therapy against stem-like/progenitor cells was achieved by using glutathione-scavenging nanoparticles, which can load and release the drug pair effectively. Overall, our study provides a framework for understanding glutathione signaling as one of the therapeutic vulnerabilities of stem-like/progenitor cells. Broadly, these findings revealed a promising arsenal by encapsulating glutathione-scavenging nanoparticles with co-targeting VEGFR2 and JMJD3 to eradicate chemotherapy-resistant osteosarcoma.

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JMJD3 in the regulation of human diseases

Cited by 78 publications

References 144 publications

Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis

Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis

Targeted inhibition of KDM6 histone demethylases eradicates tumor-initiating cells via enhancer reprogramming in colorectal cancer

Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma

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