Targeting multiple molecules in the same biological network may maximize therapeutic efficacy. In this study, we identified a 27-gene module that is highly expressed in solid tumors, encoding actionable targets including EZH2 and BIRC5. The combination of EZH2 inhibitors and a BIRC5 inhibitor, YM155, results in a remarkable synergistic effect. The action of EZH2 inhibitors in this process is independent of the histone methyltransferase activity of polycomb repressive complex 2. Our study reveals a potential therapeutic approach for treating solid tumors by simultaneously targeting EZH2 and BIRC5.
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http://dx.doi.org/10.3390/cancers15010208 | DOI Listing |
Pharmacol Res
January 2025
Department of Physiology, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, PR China. Electronic address:
Pediatric high-grade gliomas (pHGGs) are the most common brain malignancies in children and are characterized by blocked differentiation. The epigenetic landscape of pHGGs, particularly the H3K27-altered and H3G34-mutant subtypes, suggests these tumors may be particularly susceptible to strategies that target blocked differentiation. Differentiation therapy aims to overcome this differentiation blockade by promoting glioma cell differentiation into more mature and less malignant cells.
View Article and Find Full Text PDFJ Nat Med
January 2025
Chongqing Academy of Chinese Materia Medica, Chongqing University of Chinese Medicine, Chongqing, 402760, China.
Non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), and follicular lymphoma (FL), predominantly arise from B cells undergoing germinal center (GC) reactions. The transcriptional repressor B-cell lymphoma 6 (BCL6) is indispensable for GC formation and contributes to lymphomagenesis via its BTB domain-mediated suppression of target genes. Dysregulation of BCL6 underpins the pathogenesis of GC-derived NHL.
View Article and Find Full Text PDFCell Rep
January 2025
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland. Electronic address:
Polycomb repressive complex 2 (PRC2), composed of the core subunits EED, SUZ12, and either EZH1 or EZH2, is critical for maintaining cellular identity in multicellular organisms. PRC2 deposits H3K27me3, which is thought to recruit the canonical form of PRC1 (cPRC1) to promote gene repression. Here, we show that EZH1-PRC2 and cPRC1 are the primary Polycomb complexes on target genes in non-dividing, quiescent cells.
View Article and Find Full Text PDFCancers (Basel)
December 2024
Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London SW3 6JZ, UK.
There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma.
View Article and Find Full Text PDFTher Adv Med Oncol
January 2025
Department of Molecular Biology of Cancer, Medical University of Lodz, Mazowiecka 6/8, Lodz 92-215, Poland.
The enhancer of zeste homolog 2 (EZH2) is a catalytic component of Polycomb repressive complex 2 (PRC2) mediating the methylation of histone 3 lysine 27 (H3K27me3) and hence the epigenetic repression of target genes, known as canonical function. Growing evidence indicates that EZH2 has non-canonical roles that are exerted as PRC2-dependent and PRC2-independent methylation of non-histone proteins, and methyltransferase-independent interactions of EZH2 with various proteins contributing to gene expression regulation and alterations in the protein stability. is frequently mutated and/or its expression is deregulated in various cancer types.
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