Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors

Huang, Xun; Yan, Juan; Zhang, Min; Wang, Yafang; Chen, Yi; Fu, Xuhong; Wei, Rongrui; Zheng, Xingling; Liu, Zhiwei; Zhang, Xiong; Yang, Hong; Hao, Bingbing; Shen, Yanyan; Su, Yi; Cong, Xiaoji; Huang, Min; Tan, Minjia; Ding, Jian; Geng, Meiyu

doi:10.1016/j.cell.2018.08.058

Cited by 184 publications

(147 citation statements)

References 49 publications

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“…Because BRD4 and EZH2 each potently promotes IH, as demonstrated by our conditional knockout and gene transfer in vivo experiments presented herein, this BRD4/EZH2 axis is mechanistically important. In support of our finding, enhanced efficacy of combined BETs and EZH2 inhibitors has been reported in cancer research 32 . Moreover, a recent report showed that BRD4 regulated EZH2 expression by indirectly upregulating c-myc in cancer cells 19 , although it was not addressed as to whether epigenetic mechanisms were involved.…”

Section: Discussionsupporting

confidence: 91%

Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

Zhang

Wang

Urabe

et al. 2020

Preprint

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Atherosclerosis is commonly treated with angioplasty which, however, evokes neointimal hyperplasia (IH) and recurrent stenotic diseases. Epigenomic investigation was lacking on postangioplasty IH. The histone acetylation reader BRD4 and H3K27me3 writer EZH2 are potent epigenetic factors; their relationship is little understood. Through genome-wide survey in the rat angioplasty model, we studied BRD4 and EZH2 functional regulations involved in IH.We performed chromatin immunoprecipitation sequencing (ChIPseq) using rat carotid arteries. While H3K27me3 ChIPseq signal prevalently intensified in balloon-injured (vs uninjured) arteries, BRD4 and H3K27ac became more enriched at Ezh2. Indeed, BRD4-siRNA or CRISPR-deletion of BRD4-associated enhancer abated the smooth muscle cell (SMC) expression of EZH2, and SMC-specific BRD4 knockout in BRD4 fl/fl ; Myh11CreER T2 mice reduced both H3K27me3 and IH in wire-injured femoral arteries. In accordance, postangioplasty IH was exacerbated and mitigated, respectively, by lentiviral expression and pharmacological inhibition of EZH2/1; EZH2 (or EZH1) loss-and gain-of-function respectively attenuated and aggravated pro-IH SMC proliferative behaviors. Furthermore, while H3K27me3 ChIPseq signal magnified at P57 and ebbed at Ccnd1 and Uhrf1 after injury, silencing either EZH2 or EZH1 in SMCs up-regulated P57 and down-regulated Ccnd1 and Uhrf1.In summary, our results reveal an upsurge of EZH2/H3K27me3 after angioplasty, BRD4's control over EZH2 expression, and non-redundant EZH2/1 functions. As such, this study unravels angioplasty-induced loci-specific H3K27me3/ac redistribution in the epigenomic landscape rationalizing BRD4/EZH2-governed pro-IH regulations.

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Section: Discussionsupporting

confidence: 91%

Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

Zhang

Wang

Urabe

et al. 2020

Preprint

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“…A recent report demonstrated that MLL1 expression level and H3K27ac upregulation are positively correlation with resistance to EZH2 inhibition (39). In agreement with the report, our results showed that the cells that were sensitive to BR-001 expressed low level of MLL-1, whereas BR-001-resistant cells had relative high level of MLL-1 and H3K27Ac (Fig.…”

Section: Resistance To Br-001 Is Associated With H3k27 Acetylationsupporting

confidence: 93%

An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response

Dong¹,

Liu²,

Zhang³

et al. 2019

Cancer Research

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Aberrant activity of polycomb repressive complex 2 (PRC2) is involved in a wide range of human cancer progression. The WD40 repeat-containing protein EED is a core component of PRC2 and enhances PRC2 activity through interaction with H3K27me3. In this study, we report the discovery of a class of pyrimidone compounds, represented by BR-001, as potent allosteric inhibitors of PRC2. X-ray co-crystallography showed that BR-001 directly binds EED in the H3K27me3-binding pocket. BR-001 displayed antitumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice daily oral dosing with BR-001 resulted in robust antitumor activity. BR-001 was also efficacious in syngeneic CT26 colon tumor-bearing mice; oral dosing of 30 mg/kg of BR-001 led to 59.3% tumor growth suppression and increased frequency of effector CD8 þ T-cell infiltrates in tumors. Pharmacodynamic analysis revealed that CXCL10 was highly upregulated, suggesting that CXCL10 triggers the trafficking of CD8 þ T cells toward tumor sites. Our results demonstrate for the first time that inhibition of EED modulates the tumor immune microenvironment to induce regression of colon tumors and therefore has the potential to be used in combination with immune-oncology therapy.Significance: BR-001, a potent inhibitor of the EED subunit of the PRC2 complex, suppresses tumor progression by modulating the tumor microenvironment. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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“…Differential response to EZH2 small-molecule inhibitors like EI1 and GSK126 were observed in GC B cell lymphoma cell lines, owing to the activation of IGF-1R, MEK, and PI3K pathways [145], MLL1-P300/CBP-directed H3K27 acetylation gain [146] as well as secondary EZH2 mutations in wild-type and mutant EZH2 alleles [147,148].…”

Section: Ezh2 Inhibitorsmentioning

confidence: 99%

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

Chng

2019

J Hematol Oncol

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EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which along with other PRC2 components mediates gene expression suppression via the methylation of Histone H3 at lysine 27. Recent studies have revealed a dichotomous role of EZH2 in physiology and in the pathogenesis of cancer. While it plays an essential role in the development of the lymphoid system, its deregulation, whether due to genetic or non-genetic causes, promotes B cell-and T cell-related lymphoma or leukemia. These findings triggered a boom in the development of therapeutic EZH2 inhibitors in recent years. Here, we discuss physiologic and pathogenic function of EZH2 in lymphoid context, various internal causes of EZH2 aberrance and how EZH2 modulates lymphomagenesis through epigenetic silencing, post-translational modifications (PTMs), orchestrating with surrounding tumor micro-environment and associating with RNA or viral partners. We also summarize different strategies to directly inhibit PRC2-EZH2 or to intervene EZH2 upstream signaling.

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Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors

Cited by 184 publications

References 49 publications

Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

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