Therapeutic potential of enhancer of zeste homolog 2 in autoimmune diseases

Yang, Yuexin; Shen, Hui‐Hui; Cao, Fan; Xie, Liangyu; Zhu, Guang-Lin; Sam, Napoleon Bellua; Wang, Deguang; Pan, Hai‐Feng

doi:10.1080/14728222.2019.1696309

Cited by 17 publications

(9 citation statements)

References 169 publications

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“…As the central component of PRC2, EZH2 is involved in numerous epigenetic modifications that are associated with cell proliferation, differentiation, survival, adhesion, and DNA damage repair. 414 Dysfunction of EZH2 is closely related to tumorigenesis and progression. Accumulating evidence has confirmed that EZH2 is frequently mutated and abnormally overexpressed in various malignant tumors including prostate cancer, 415,416 ovarian cancer, 417 endometrial carcinoma, 418 breast cancer, 419 melanoma as well as hematological malignancies, 420 such as NHL, B-cell lymphoma, and T-cell ALL.…”

Section: Ezh2 Inhibitorsmentioning

confidence: 99%

“…Exploring various effective combination strategies, including combination with chemotherapy, immunotherapy, kinase targeted therapy, and metabolic regulators, is a promising direction in the near future. 414,439,440 HDAC inhibitors Histone deacetylases (HDACs) are important epigenetic regulators that remove the acetyl groups from the N-acetylated lysine residues of histones and various non-histone substrates. To date, 18 HDACs have been identified in mammals and are characterized into 4 subfamilies: class I HDACs (HDACs 1, 2, 3, 8), class II HDACs (class IIa: HDACs 4, 5, 7, 9; class IIb: HDACs 6, 10), class III HDACs (Sirt1-7) and class IV HDAC (HDAC11).…”

Section: Ezh2 Inhibitorsmentioning

confidence: 99%

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Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

962

490

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Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

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Section: Ezh2 Inhibitorsmentioning

confidence: 99%

Section: Ezh2 Inhibitorsmentioning

confidence: 99%

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

962

490

View full text Add to dashboard Cite

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“…EZH2, a subunit of the polycomb repressive complex 2 that transfers methyl groups to lysine groups on histone tails, is under investigation in multiple clinical trials as a new cancer drug [79,111]. Interestingly, EZH2 inhibition has also been proposed as a treatment candidate for a number of autoimmune diseases, because of its role in autoimmune self-tolerance [112]. Similarly, PRMTs, which catalyze the transfer of methyl groups to arginine residues on histone tails, are being inhibited by a number of small molecules in clinical trials of several malignancies [78].…”

Section: Interpreting Mutations Located In Enhancersmentioning

confidence: 99%

Enhancers in disease: molecular basis and emerging treatment strategies

Claringbould

Zaugg

2021

Trends in Molecular Medicine

121

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Enhancers are genomic sequences that play a key role in regulating tissue-specific gene expression levels. An increasing number of diseases are linked to impaired enhancer function through chromosomal rearrangement, genetic variation within enhancers, or epigenetic modulation. Here, we review how these enhancer disruptions have recently been implicated in congenital disorders, cancers, and common complex diseases and address the implications for diagnosis and treatment. Although further fundamental research into enhancer function, target genes, and context is required, enhancer-targeting drugs and gene editing approaches show great therapeutic promise for a range of diseases. HighlightsEnhancer disruption is increasingly implicated as a disease-driving mechanism. Chromosomal rearrangements can cause an enhancer to drive aberrant gene expression, genetic variants in enhancers can impact a transcription factor binding site, and disease-associated epigenetic changes are enriched in enhancer regions.The three big challenges in enhancer research focus on systematically identifying functional enhancers, their target genes, and the context in which they are active.Bromo-and extra-terminal (BET) inhibitors are a new class of drugs that target enhancers and inhibit gene expression. They are under investigation as treatment for cancer and other diseases.Gene editing techniques elucidate enhancer function and are being used to selectively regulate or mutate disturbed enhancers.

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“…Targeting EZH2 enhances cAMP response element-binding protein to inhibit the ulcerative colitis progression[ 17 ]. It has been well-recognized that EZH2 presents a critical biological significance of in autoimmune disorders and cancer, and thereby targeting EZH2 is a promising therapeutic strategy in these diseases[ 18 , 19 ]. In this study, we demonstrated that the depletion of EZH2 inhibited DSS-induced colitis in vivo.…”

Section: Discussionmentioning

confidence: 99%

Enhancer of zeste homolog 2 contributes to apoptosis by inactivating janus kinase 2/ signal transducer and activator of transcription signaling in inflammatory bowel disease

Zhou

Yang

Wang

et al. 2021

WJG

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BACKGROUND Inflammatory bowel disease (IBD) is a prevalent worldwide health problem featured by relapsing, chronic gastrointestinal inflammation. Enhancer of zeste homolog 2 (EZH2) is a critical epigenetic regulator in different pathological models, such as cancer and inflammation. However, the role of EZH2 in the IBD development is still obscure. AIM To explore the effect of EZH2 on IBD progression and the underlying mechanism. METHODS The IBD mouse model was conducted by adding dextran sodium sulfate (DSS), and the effect of EZH2 on DSS-induced colitis was assessed in the model. The function of EZH2 in regulating apoptosis and permeability was evaluated by Annexin V-FITC Apoptosis Detection Kit, transepithelial electrical resistance analysis, and Western blot analysis of related markers, including Zona occludens 1, claudin-5, and occludin, in NCM460 and fetal human colon (FHC) cells. The mechanical investigation was performed by quantitative reverse transcription - polymerase chain reaction, Western blot analysis, and chromatin immunoprecipitation assays. RESULTS The colon length was inhibited in the DSS-treated mice and was enhanced by the EZH2 depletion in the system. DSS treatment caused a decreased histological score in the mice, which was reversed by EZH2 depletion. The inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interleukin-1β, were induced in the DSS-treated mice, in which the depletion of EZH2 could reverse this effect. Moreover, the tumor necrosis factor-α treatment induced the apoptosis of NCM460 and FHC cells, in which EZH2 depletion could reverse this effect in the cells. Moreover, the depletion of EZH2 attenuated permeability of colonic epithelial cells. Mechanically, the depletion of EZH2 or EZH2 inhibitor GSK343 was able to enhance the expression and the phosphorylation of janus kinase 2 (JK2) and signal transducer and activator of transcription in the NCM460 and FHC cells. Specifically, EZH2 inactivated JAK2 expression by regulating histone H3K27me3. JAK2 inhibitor TG101348 was able to reverse EZH2 knockdown-mediated colonic epithelial cell permeability and apoptosis. CONCLUSION Thus, we concluded that EZH2 contributed to apoptosis and inflammatory response by inactivating JAK2/ signal transducer and activator of transcription signaling in IBD. EZH2 may be applied as a potential target for IBD therapy.

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Therapeutic potential of enhancer of zeste homolog 2 in autoimmune diseases

Cited by 17 publications

References 169 publications

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Enhancers in disease: molecular basis and emerging treatment strategies

Enhancer of zeste homolog 2 contributes to apoptosis by inactivating janus kinase 2/ signal transducer and activator of transcription signaling in inflammatory bowel disease

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