Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response
Cristalli, Camilla (IRCCS Istituto Ortopedico Rizzoli)
Manara, Maria Cristina (IRCCS Istituto Ortopedico Rizzoli)
Valente, Sergio (Sapienza University of Rome)
Pellegrini, Evelin (IRCCS Istituto Ortopedico Rizzoli)
Bavelloni, Alberto (IRCCS Istituto Ortopedico Rizzoli)
De Feo, Alessandra (IRCCS Istituto Ortopedico Rizzoli)
Blalock, William (Istituto di Genetica Molecolare-Luigi Luca Cavalli Sforza)
Di Bello, Elisabetta (Sapienza University of Rome)
Piñeyro, David (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Merkel, Angelika (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Esteller, M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Tirado, Oscar M. (Institut d'Investigació Biomèdica de Bellvitge)
Mai, Antonello (Sapienza University of Rome)
Scotlandi, Katia (IRCCS Istituto Ortopedico Rizzoli)

Date:	2022
Abstract:	DNA methylation is an important component of the epigenetic machinery that regulates the malignancy of Ewing sarcoma (EWS), the second most common primary bone tumor in children and adolescents. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming and the DNMT1 enzyme has been demonstrated to have an important role in both maintaining the epigenome and controlling cell cycle. Here, we showed that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 induces a specific depletion of DNMT1 and affects EWS tumor proliferation through a mechanism that is independent on DNA methylation. Depletion of DNMT1 causes perturbation of the cell cycle, with an accumulation of cells in the G1 phase, and DNA damage, as revealed by the induction of γH2AX foci. These effects elicited activation of p53-dependent signaling and apoptosis in p53wt cells, while in p53 mutated cells, persistent micronuclei and increased DNA instability was observed. Treatment with MC3343 potentiates the efficacy of DNA damaging agents such as doxorubicin and PARP-inhibitors (PARPi). This effect correlates with increased DNA damage and synergistic tumor cytotoxicity, supporting the use of the DNMTi MC3343 as an adjuvant agent in treating EWS.
Note:	The research leading to these results has received funding from AIRC under IG 2019 - ID. 22805 project - P.I., Katia Scotlandi, and Ministry of University and Research under FISR2019_00374 MeDyCa project - P.I. Antonello Mai. The authors would also thank Cristina Ghinelli for graphic support.
Note:	Altres ajuts: This work was supported by the Italian Ministry of Health (RF-2016-02361373).
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Ewing sarcoma ; Epigenetic therapies ; DNA methylation ; DNMT inhibitors ; DNA damage ; Drug synergism ; Doxorubicin ; PARP inhibitors
Published in:	Frontiers in endocrinology, Vol. 13 (31 2022) , p. 876602, ISSN 1664-2392

DOI: 10.3389/fendo.2022.876602
PMID: 35712255

12 p, 12.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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