EZH2 inhibition sensitizes retinoic acid-driven senescence in synovial sarcoma.

Autor: Mushtaq M; Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden. muhammad.mushtaq1@buitms.edu.pk.; Department of Biotechnology, Faculty of Life Sciences and Informatics. Balochistan University of Information Technology, Engineering, and Management Sciences (BUITEMS), 87300, Quetta, Pakistan. muhammad.mushtaq1@buitms.edu.pk., Liaño-Pons J; Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden. judit.liano.pons@ki.se., Wang J; Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden., Alzrigat M; Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden., Yuan Y; Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden., Ruiz-Pérez MV; Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden., Chen Y; Department of Oncology-Pathology, Karolinska Institutet, Solna, SE-171 76, Stockholm, Sweden.; Division of Hematology and Oncology, Department of Medicine, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, USA., Kashuba E; Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden.; RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of NAS of Ukraine, 03022, Kyiv, Ukraine., Haglund de Flon F; Department of Oncology-Pathology, Karolinska Institutet, Solna, SE-171 76, Stockholm, Sweden., Brodin B; Department of Applied Physics, Biomedical and X-Ray Physics, KTH Royal Institute of Technology, SE-10691, Stockholm, Sweden., Arsenian-Henriksson M; Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden. marie.arsenian.henriksson@ki.se.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Nov 16; Vol. 15 (11), pp. 836. Date of Electronic Publication: 2024 Nov 16.
DOI: 10.1038/s41419-024-07176-6
Abstrakt: Synovial sarcoma (SS) is driven by a unique t(18;X) chromosomal translocation resulting in expression of the SS18-SSX fusion oncoprotein, a transcriptional regulator with both activating and repressing functions. However, the manner in which SS18-SSX contributes to the development of SS is not entirely known. Here, we show that SS18-SSX drives the expression of Preferentially Expressed Antigen in Melanoma (PRAME), which is highly expressed in SS but whose function remains poorly understood. The fusion protein directly binds and activates the PRAME promoter and we found that expression of SS18-SSX and PRAME are positively correlated. We provide evidence that PRAME modulates retinoic acid (RA) signaling, forming a ternary complex with the RA receptor α (RARα) and the Enhancer of Zeste Homolog 2 (EZH2). Knockdown of PRAME suppressed the response to all-trans retinoic acid (ATRA) supporting PRAME's role in modulating RA-signaling. Notably, we demonstrate that combined pharmacological inhibition of EZH2 and treatment with ATRA reconstituted RA signaling followed by reduced proliferation and induction of cellular senescence. In conclusion, our data provides new insights on the role of the SS18-SSX fusion protein in regulation of PRAME expression and RA signaling, highlighting the therapeutic potential of disrupting the RARα-PRAME-EZH2 complex in SS. Schematic presentation of the proposed model. A The RARα-PRAME-EZH2 ternary complex in SS. The fusion SS18-SSX oncoprotein binds to the PRAME promoter and activates its expression. PRAME in turn interacts with RARα-RXR heterodimers as well as with EZH2, and the complex binds to retinoic acid response elements (RAREs) in the DNA. This results in transcriptional repression of retinoic acid (RA) responsive genes and thus inhibition of RA-signaling, allowing tumor cell proliferation. B Therapeutic strategy. Treatment with an EZH2 inhibitor, such as GSK343, or activation of RAR receptors via all-trans retinoic acid (ATRA), disrupts the RARα-PRAME-EZH2 ternary complex and restores RA-signaling. Exposure to GSK343 or ATRA results in inhibition of cell proliferation and induction of cellular senescence, where GSK343 shows a dominant effect. The Figure was created with Biorender.com.
Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate This study does not involve any human participants, animals, or identifiable personal data, and thus did not require ethics committee approval or informed consent. The data analyzed were publicly available, and no new data collection from individuals was conducted. We have ensured that our study adheres to all relevant ethical standards.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: