The role and prospect of JMJD3 in stem cells and cancer

Yin, Xiaojiao; Yang, Siyu; Zhang, Mingyue; Ye, Ying

doi:10.1016/j.biopha.2019.109384

Cited by 49 publications

(39 citation statements)

References 100 publications

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“…Based on the bioinformatics analysis and the dualluciferase reporter gene assay in the present study, miR-27b could target Jumonji D3 (JMJD3), a histone lysine demethylase, regulates transcription and actives the expression of genes via demethylating H3K27me3 [22][23][24]. More importantly, JMJD3 has been reported to play a critical role in the epigenetic regulation during sepsis [25,26].…”

Section: Introductionmentioning

confidence: 80%

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

Sun

Chen

et al. 2021

Stem Cell Res Ther

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Background Exosomal microRNAs (miRs) derived from mesenchymal stem cells (MSCs) have been shown to play roles in the pathophysiological processes of sepsis. Moreover, miR-27b is highly enriched in MSC-derived exosomes. Herein, we aimed to investigate the potential role and downstream molecular mechanism of exosomal miR-27b in sepsis. Methods Inflammation was induced in bone marrow-derived macrophages (BMDMs) by lipopolysaccharide (LPS), and mice were made septic by cecal ligation and puncture (CLP). The expression pattern of miR-27b in MSC-derived exosomes was characterized using RT-qPCR, and its downstream gene was predicted by in silico analysis. The binding affinity between miR-27b, Jumonji D3 (JMJD3), or nuclear factor κB (NF-κB) was characterized to identify the underlying mechanism. We induced miR-27b overexpression or downregulation, along with silencing of JMJD3 or NF-κB to examine their effects on sepsis. The production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 was detected by ELISA. Results miR-27b was highly expressed in MSC-derived exosomes. Mechanistic investigations showed that miR-27b targeted JMJD3. miR-27b decreased expression of pro-inflammatory genes by inhibiting the recruitment of JMJD3 and NF-κB at gene promoter region. Through this, MSC-derived exosomal miR-27b diminished production of pro-inflammatory cytokines in LPS-treated BMDMs and septic mice, which could be rescued by upregulation of JMJD3 and NF-κB. Besides, in vitro findings were reproduced by in vivo findings. Conclusion These data demonstrated that exosomal miR-27b derived from MSCs inhibited the development of sepsis by downregulating JMJD3 and inactivating the NF-κB signaling pathway.

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Section: Introductionmentioning

confidence: 80%

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

Sun

Chen

et al. 2021

Stem Cell Res Ther

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“…EZH2 is an enzymatic catalytic subunit of PRC2 that can alter gene expression by trimethylation of Lys-27 in histone 3 (H3K27me3) [2]. H3K27me3 is associated with repression of genes expression and regarded as a critical epigenetic event during tissue development and stem cell fate determination [3]. Besides H3K27me3, PRC2 also methylates non-histone protein substrates, including the transcription factor GATA4 [4].…”

Section: Introductionmentioning

confidence: 99%

EZH2: a novel target for cancer treatment

2020

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Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-todate findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.

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“…The cellular dynamics of H3K27me3 is achieved through precise control of the activities of both polycomb complex 2 (PRC2) that writes this code and lysine demethylase 6 (KDM6) family proteins that specifically removes it 9 , 10 . Importantly, distorted H3K27me3 landscape due to alterations in PRC2 subunits and two KDM6 enzymes (KDM6A or UTX, KDM6B or JMJD3) has been observed in the vast majority of human cancers 11 - 13 . Thus, therapeutic potential of counteracting hyper PRC2 activity, such as EZH2 inhibitors, in cancer has been under intensive investigation for the past decades 14 , whereas strategies targeting KDM6 in cancer treatment that just emerged in recent few years surprisingly have already demonstrated promising effect against various cancer types, including glioma 15 - 17 , neuroblastoma 18 , acute myeloid leukemia 19 , and castration resistant prostate cancer 20 .…”

Section: Introductionmentioning

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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The role and prospect of JMJD3 in stem cells and cancer

Cited by 49 publications

References 100 publications

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway

EZH2: a novel target for cancer treatment

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

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