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Keywords = tazemetostat (EPZ-6438)

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19 pages, 3319 KB  
Article
EZH2 Inhibition in Mesothelioma Cells Increases the Release of Extracellular Vesicles That Skew Neutrophils Toward a Protumor Phenotype
by Giulia Pinton, Elia Bari, Silvia Fallarini, Valentina Gigliotti, Veronica De Giorgis, Fausto Chiazza, Maria Luisa Torre, Marcello Manfredi and Laura Moro
Int. J. Mol. Sci. 2025, 26(21), 10328; https://doi.org/10.3390/ijms262110328 - 23 Oct 2025
Viewed by 688
Abstract
We previously demonstrated that in BAP1-proficient pleural mesothelioma cells, CDKN2A is critical for mediating the response to selective EZH2 inhibition and highlighted a complex interplay between epigenetic regulation and the tumor immune microenvironment. In this study, we employed a quantitative proteomic mass spectrometry [...] Read more.
We previously demonstrated that in BAP1-proficient pleural mesothelioma cells, CDKN2A is critical for mediating the response to selective EZH2 inhibition and highlighted a complex interplay between epigenetic regulation and the tumor immune microenvironment. In this study, we employed a quantitative proteomic mass spectrometry approach to assess alterations in protein expression following EZH2 inhibition in BAP1- and CDKN2A-proficient mesothelioma cells cultured as spheroids. Additionally, we analyzed extracellular vesicles (EVs), which were isolated through tangential flow filtration. Flow cytometric analysis and co-culture systems were used to characterize the effects of EVs on neutrophils. Upon EZH2 inhibition, we demonstrated RAB27b and CD63 upregulation and increased release of extracellular vesicles. We found that a brief exposure to EVs derived from EZH2 inhibitor-treated cells skewed naïve neutrophils toward a pro-tumor phenotype characterized by high levels of PD-L1 and MSLN (Mesothelin) expression on the surface. These EV-elicited neutrophils suppressed T cell proliferation while enhancing tumor cell growth. Moreover, we observed changes in the EV cargo derived from EZH2 inhibitor-treated spheroids. Our findings highlight the significant role of EVs in creating an immunosuppressive microenvironment, and underscore the urgent need for further investigation into the regulation of neutrophil biology and function in the PM. Full article
(This article belongs to the Special Issue Advances and Insights in Tumorigenesis and Tumor Metastasis)
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25 pages, 6794 KB  
Article
Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids
by Silvia Mola, Giulia Pinton, Marco Erreni, Marco Corazzari, Marco De Andrea, Ambra A. Grolla, Veronica Martini, Laura Moro and Chiara Porta
Int. J. Mol. Sci. 2021, 22(9), 4391; https://doi.org/10.3390/ijms22094391 - 22 Apr 2021
Cited by 20 | Viewed by 4426
Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct [...] Read more.
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes’ recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2. Full article
(This article belongs to the Special Issue Immune Response to Cancer: From Tumor Onset to Therapeutic Approach)
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11 pages, 1846 KB  
Communication
The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice
by Seul Lee, Dong-Cheol Woo, Jeeheon Kang, Moonjin Ra, Ki Hyun Kim, Seoung Rak Lee, Dong Kyu Choi, Heejin Lee, Ki Bum Hong, Sang-Hyun Min, Yongjun Lee and Ji Hoon Yu
Biology 2020, 9(5), 93; https://doi.org/10.3390/biology9050093 - 2 May 2020
Cited by 27 | Viewed by 6298
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH. Full article
(This article belongs to the Section Cell Biology)
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