A novel EZH2 inhibitor induces synthetic lethality and apoptosis in PBRM1-deficient cancer cells

Huang, Kejia; Sun, Rong; Chen, Jia‐Rong; Yang, Qianye; Wang, Yucheng; Zhang, Yang; Xie, Kun; Zhang, Tiantian; Li, Rui; Zhao, Qi; Zou, Liang; Li, Jian

doi:10.1080/15384101.2020.1729450

Cited by 23 publications

(14 citation statements)

References 39 publications

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“…PBRM1 is characterized by six bromodomains in tandem, two BAH domains, and an HMG domain [ 272 , 313 ], and mutations affecting this subunit have been identified in >40% of renal cell carcinoma [ 314 ]. Recently, synthetic lethality and apoptosis in PBRM1-deficient cancer cells have been induced by a specific EZH2 inhibitor [ 315 ]. Of note, BRD7, which also contains a bromodomain, is a tumor suppressor identified in a subset of breast cancers lacking p53 mutations [ 316 , 317 ].…”

Section: Dissonances In Chromatin Remodeling In Cancermentioning

confidence: 99%

Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer

Clapier

2021

IJMS

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The establishment and maintenance of genome packaging into chromatin contribute to define specific cellular identity and function. Dynamic regulation of chromatin organization and nucleosome positioning are critical to all DNA transactions—in particular, the regulation of gene expression—and involve the cooperative action of sequence-specific DNA-binding factors, histone modifying enzymes, and remodelers. Remodelers are molecular machines that generate various chromatin landscapes, adjust nucleosome positioning, and alter DNA accessibility by using ATP binding and hydrolysis to perform DNA translocation, which is highly regulated through sophisticated structural and functional conversations with nucleosomes. In this review, I first present the functional and structural diversity of remodelers, while emphasizing the basic mechanism of DNA translocation, the common regulatory aspects, and the hand-in-hand progressive increase in complexity of the regulatory conversations between remodelers and nucleosomes that accompanies the increase in challenges of remodeling processes. Next, I examine how, through nucleosome positioning, remodelers guide the regulation of gene expression. Finally, I explore various aspects of how alterations/mutations in remodelers introduce dissonance into the conversations between remodelers and nucleosomes, modify chromatin organization, and contribute to oncogenesis.

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Section: Dissonances In Chromatin Remodeling In Cancermentioning

confidence: 99%

Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer

Clapier

2021

IJMS

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“…To assess the potential of the two selected compounds from the molecular docking simulations we identified for each of these compounds the specific interactions that they established with each of the proteins. We compared these data with information obtained from X-ray cocrystallised structures with known inhibitors as well as with results already gathered from the several molecular docking simulations performed by other groups to gain insight into EZH2 [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ] and P20S inhibition [ 32 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

et al. 2021

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Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited clinical efficacy due to acquired resistance. One of the solutions to overcome this problem is a polypharmacology approach, namely combination therapy and multitargeting drugs. Several polypharmacology avenues are currently being explored. The simultaneous inhibition of EZH2 and Proteasome 20S remains to be investigated, despite the encouraging evidence of therapeutic synergy between the two. Therefore, we sought to bridge this gap by proposing a holistic in silico strategy to find new dual-target inhibitors. First, we assessed the characteristics of both pockets and compared the chemical space of EZH2 and Proteasome 20S inhibitors, to establish the feasibility of dual targeting. This was followed by molecular docking calculations performed on EZH2 and Proteasome 20S inhibitors from ChEMBL 25, from which we derived a predictive model to propose new EZH2 inhibitors among Proteasome 20S compounds, and vice versa, which yielded two dual-inhibitor hits. Complementarily, we built a machine learning QSAR model for each target but realised their application to our data is very limited as each dataset occupies a different region of chemical space. We finally proceeded with molecular dynamics simulations of the two docking hits against the two targets. Overall, we concluded that one of the hit compounds is particularly promising as a dual-inhibitor candidate exhibiting extensive hydrogen bonding with both targets. Furthermore, this work serves as a framework for how to rationally approach a dual-targeting drug discovery project, from the selection of the targets to the prediction of new hit compounds.

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“…Overexpression of EZH2 has been linked to various types of solid tumors including glioblastoma, soft tissue sarcoma, melanoma and breast and prostate cancers [21][22][23]. Previous reports have shown that EZH2 is highly integrated into various signaling pathways in cancer, including and not limited to, cell proliferation, cell survival, invasion, migration, epithelial to mesenchymal transition and drug resistance [24][25][26][27][28]. Current evidence suggests a central role of EZH2 in the development of pediatric soft tissue sarcomas and glioblastoma [29,30].…”

Section: Introductionmentioning

confidence: 99%

Targeting EZH2-mediated methylation of histone 3 inhibits proliferation of pediatric acute monocytic leukemia cells in vitro

Ghabkari

Narendran

2021

Preprint

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Background: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and a catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the mono-, di-, and tri-methylation of histone H3 at Lys 27 (H3K27me3) to facilitate chromatin remodeling and gene silencing functions. The overexpression of EZH2 is associated with high levels of H3K27me3 in various types of cancers. Previous reports showed a significant association of EZH2 aberrations in pediatric cancers such as soft tissue sarcomas and glioblastoma. Recent reports in human subjects and animal models have also suggested a central role of EZH2 in the induction and progression of acute myeloid leukemia. Methods: In this study, we aimed to investigate the molecular status of EZH in cell lines derived from distinct pediatric leukemia to assess the efficacy of targeting EZH2 to suppress cancer cell survival and proliferation. Cell cytotoxicity and the half maximal inhibitory concentration (IC50) were measured by Alamar blue cytotoxicity assay. The molecular status of EZH2 was profiled by DNA sequencing and western blot analysis of EZH2 protein levels in THP-1, SEM, and MV4:11. In addition, Methylation of histone H3 was evaluated by immunoblotting and immunostaining analyses. Results: Our results showed that EZH2 protein is overexpressed in the pediatric monocytic cell line THP-1 , but not in other leukemia derived cell lines MV4;11 and SEM. Screening a panel of methyltransferase inhibitors revealed that three inhibitors; GSK126, UNC1999 and EPZ-5687 are the most potent inhibitors that suppressed EZH2 activity selectively on lysine 27 which resulted in increased apoptosis and inhibition of AKT and ERK protein phosphorylation in THP-1 cells. Our data demonstrated a significant increase in apoptosis in cells treated with drug combination (EZH2i and selinexor) compared to EZH2i inhibitors alone. Conclusions: Taken together, our data provide initial evidence that targeting EZH2 is a promising therapeutic strategy for the treatment of subtypes of pediatric AML. Also, combining EZH2 inhibitors with selinexor may increase the treatment efficacy in these patients. Findings from this study indicate further evaluation and consideration of these compounds for early phase clinical studies in selected pediatric malignancies in the future.

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A novel EZH2 inhibitor induces synthetic lethality and apoptosis in PBRM1-deficient cancer cells

Cited by 23 publications

References 39 publications

Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer

Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

Targeting EZH2-mediated methylation of histone 3 inhibits proliferation of pediatric acute monocytic leukemia cells in vitro

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