Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Liu, Yongfeng; Peng, Junjie; Sun, Tongyu; Li, Ni; Zhang, Le; Ren, Jiale; Yuan, Huairui; Kan, Shan; Pan, Qiang; Li, Xiang; Ding, Yong; Jiang, Min; Cong, Xiaoji; Tan, Minjia; Ma, Yu‐Shui; Fu, Da; Cai, Sanjun; Xiao, Yichuan; Wang, Xiaoming; Qin, Jun

doi:10.1073/pnas.1700909114

Cited by 81 publications

(86 citation statements)

References 44 publications

(54 reference statements)

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“…However, we observed that EZH2 deficiency diminished genomic stability and induced apoptosis in cloned embryos. It was previously shown that EZH2 acts as an epigenetic determinant by inhibiting TNF-a-mediated apoptosis in colitis (47) and maintained T-cell genomic integrity by modulating DNA damage-induced apoptosis (34). Our findings highlight the important role of EZH2 for maintaining genomic stability and inhibiting apoptosis after SCNT reprogramming.…”

Section: Discussionsupporting

confidence: 61%

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

et al. 2019

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Aberrant epigenetic reprogramming is a major factor of developmental failure of cloned embryos. Histone H3 lysine 27 trimethylation (H3K27me3), a histone mark for transcriptional repression, plays important roles in mammalian embryonic development and induced pluripotent stem cell (iPSC) generation. The global loss of H3K27me3 marks may facilitate iPSC generation in mice and humans. However, the H3K27me3 level and its role in bovine somatic cell nuclear transfer (SCNT) reprogramming remain poorly understood. Here, we show that SCNT embryos exhibit global H3K27me3 hypermethylation from the 2‐ to 8‐cell stage and that its removal by ectopically expressed H3K27me3 lysine demethylase (KDM)6A greatly improves nuclear reprogramming efficiency. In contrast, H3K27me3 reduction by H3K27me3 methylase enhancer of zeste 2 polycomb repressive complex knockdown or donor cell treatment with the enhancer of zeste 2 polycomb repressive complex—selective inhibitor GSK343 suppressed blastocyst formation by SCNT embryos. KDM6A overexpression enhanced the transcription of genes involved in cell adhesion and cellular metabolism and X‐linked genes. Furthermore, we identified methyl‐CpG‐binding domain protein 3‐like 2, which was reactivated by KDM6A, as a factor that is required for effective reprogramming in bovines. These results show that H3K27me3 functions as an epigenetic barrier and that KDM6A overexpression improves SCNT efficiency by facilitating transcriptional reprogramming.—Zhou, C., Wang, Y., Zhang, J., Su, J., An, Q., Liu, X., Zhang, M., Wang, Y., Liu, J., Zhang, Y. H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency. FASEB J. 33, 4638–4652 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 61%

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

et al. 2019

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“…36 Furthermore, a recent research has reported that EZH2 is indispensable for maintaining epithelial cell barrier integrity under the condition of inflammatory, and decreasing the level of EZH2 could block the protective role of the NF-κB signaling pathway in cell survival. 37 Increasing evidence has suggested that EZH2 is a potential target in cancer therapy. In this present study, we certified that DUB3 could regulate the proliferation and apoptosis of OSCC cell lines via boosting the production of EZH2.…”

Section: Discussionmentioning

confidence: 99%

<p>DUB3 Facilitates Growth and Inhibits Apoptosis Through Enhancing Expression of EZH2 in Oral Squamous Cell Carcinoma</p>

Luo¹,

Zhou²,

Cai³

et al. 2020

OTT

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Background: Here, we probed the action mechanism of ubiquitin-specific processing proteases 17 (DUB3) in the evolution of oral squamous cell carcinoma (OSCC). Methods: The expression of genes were calculated by qRT-PCR, and proteins were assessed by Western blot and immunohistochemistry. The cells viability and proliferation were checked by MTT and EdU assay, respectively. Flow cytometry was implemented to detect the cell cycle and apoptosis. The activity of EZH2 gene promoter was measured by luciferase reporter assay. Co-immunoprecipitation assay was used to ensure the ubiquitination of bromodomain-containing protein 4 (BRD4). The cell apoptosis of tumor tissues was assessed by TUNEL assay. Results: DUB3 was overexpressed in OSCC tissues and cell lines, and negatively correlated with patient's survival time. DUB3 downregulation could effectively curb OSCC cells viability and proliferation, promote cell apoptosis and the expression of cleaved-caspase-3, cleaved PARP and p21, while inhibit cyclin D1. Besides, DUB3 production was positivity correlated with enhancer of zeste homolog-2 (EZH2) and BRD4. BRD4 downregulation could repress DUB3-induced EZH2 production, and MG132 reversed DUB3 decreasingmediated BRD4 downregulation. Downregulation of DUB3 promoted BRD4 ubiquitination. DUB3 promoted OSCC cells proliferation, while suppressing apoptosis via facilitating EZH2 production. At last, in vivo experiment indicated that the downregulation of DUB3 significantly inhibited the growth of xenograft tumor. Conclusion: In summary, we found that DUB3 enhanced OSCC cells proliferation and xenograft tumor growth, while inhibited their apoptosis via promoting BRD4-mediated upregulation of EZH2. Our study indicated that DUB3 may be an effective anti-cancer target for OSCC therapy.

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“…EZH2 promoted tumorigenesis by altering the expression of numerous tumor suppressor genes. Thus, the inhibition of EZH2 expression has been shown to be involved in the control of growth and progression of several cancer types [18][19][20]48], suggesting a critical role of this molecule. Previous studies indicated that , and vehicle-treated xenografts derived from nude mice are shown.…”

Section: Discussionmentioning

confidence: 99%

“…The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase unit of polycomb repressor complexes that has been shown to pocess oncogenic and tumor promoter effects through multiple mechanisms, resulting in stimulated growth and tumor progression in various cancer types [18][19][20]. Increasing evidence indicated that elevated expression of EZH2 was observed in many malignant tumors and was significantly associated with poor outcome in cancer patients [21].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

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Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

Xiao

Zheng

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: We previously showed that the major bioactive compound of Atractylodes macrocephula Koidz atractylenolide 1 (ATL-1) inhibited human lung cancer cell growth by suppressing the gene expression of 3-Phosphoinositide dependent protein kinase-1 (PDK1 or PDPK1). However, the potentially associated molecules and downstream effectors of PDK1 underlying this inhibition, particularly the mechanism for enhancing the anti-tumor effects of epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs), remain unknown. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Western blot analyses were performed to examine the protein expressions of PDK1 and of zeste homolog 2 (EZH2). The levels of long non-coding RNA (lncRNA) and HOX transcript antisense RNA (HOTAIR) were examined via qRT-PCR. RNA-binding protein immunoprecipitation assays were used to analyze HOTAIR interaction with EZH2. The promoter activity of the EZH2 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expressions of PDK1, HOTAIR, and EZH2 were conducted via transient transfection assays. A xenografted tumor model was used to further evaluate the effect of ATL-1 in the presence or absence of erlotinib in vivo. Results: We showed that the combination of ATL-1 and EGFR-TKI erlotinib further inhibited growth and induced cell arrest of the human lung cancer cells, determined by both MTT and flow cytometry assays. ATL-1 inhibited the protein expression and the promoter activity of EZH2, which was reversed in cells with PDK1 overexpression. Interestingly, ATL-1 inhibited the expression levels of HOTAIR. While silencing HOTAIR inhibited the expressions of PDK1 and EZH2, overexpression of HOTAIR reduced the ATL-1-reduced PDK1 and EZH2 protein expressions and EZH2 promoter activity. In addition, ATL-1 reduced the HOTAIR binding to the EZH2 protein. Moreover, we found that exogenously expressed EZH2 antagonized the effect of ATL-1 on cell growth inhibition. Consistent with the in vitro results, ATL-1 inhibited tumor growth and the expression levels of HOTAIR, protein expressions of EZH2 and PDK1 in vivo. Importantly, there was synergy of the combination of ATL-1 and erlotinib in this process. Conclusion: Here, we provide the first evidence that ATL-1 inhibits lung cancer cell growth through inhibiting not only the PDK1 but also the lncRNA HOTAIR, which results in the reduction of one downstream effector EZH2 expression. The novel interplay between the HOTAIR and EZH2, as well as repressions of the PDK1 and HOTAIR coordinate the overall effects of ATL-1. Importantly, the combination of ATL-1 and EGFR-TKI erlotinib exhibits synergy. Thus, targeting the PDK1- and HOTAIR-mediated downstream molecule EZH2 by the combination of ATL-1 and erlotinib potentially facilitates the development of an additional novel strategy to combat lung cancer.

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Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Cited by 81 publications

References 44 publications

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

<p>DUB3 Facilitates Growth and Inhibits Apoptosis Through Enhancing Expression of EZH2 in Oral Squamous Cell Carcinoma</p>

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

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