Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Re-cently, we demonstrated the overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) in RMS tumour biopsies and cell lines compared to normal skeletal muscle. Radiotherapy may often fail due to the abnormal expression of some molecules able to drive resistance mechanisms. The aim of this study was to analyse the involvement of DNMT3A and DNMT3B in radioresistance in RMS. RNA interference experiments against DNMT3A/3B were performed in embryonal RMS cells, upon ionizing radiation (IR) exposure and the effects of the combined treatment on RMS cells were analysed. DNMT3A and DNMT3B knocking down increased the sensitivity of RMS cells to IR, as indicated by the drastic decrease of colony formation ability. In-terestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular se-nescence program by up-regulating p16 and p21, whilst DNMT3B depletion induces significant DNA damage and impairs the DNA repair machinery (ATM, DNA-PKcs and Rad51 reduction). Our findings demonstrate for the first time that DNMT3A and DNMT3B overexpression may contribute to radiotherapy failure, and their inhibition might be a promising radiosensitizing strategy, mainly in the treatment of patients with metastatic or recurrent RMS tumours. ©

Dnmt3a and dnmt3b targeting as an effective radiosensitizing strategy in embryonal rhabdomyosarcoma / Camero, Simona; Vitali, Giulia; Pontecorvi, Paola; Ceccarelli, Simona; Anastasiadou, Eleni; Cicchetti, Francesca; Flex, Elisabetta; Pomella, Silvia; Cassandri, Matteo; Rota, Rossella; Marampon, Francesco; Marchese, Cinzia; Schiavetti, Amalia; Megiorni, Francesca. - In: CELLS. - ISSN 2073-4409. - 10:11(2021). [10.3390/cells10112956]

Dnmt3a and dnmt3b targeting as an effective radiosensitizing strategy in embryonal rhabdomyosarcoma

Simona Camero;Giulia Vitali;Paola Pontecorvi;Simona Ceccarelli;Eleni Anastasiadou;Matteo Cassandri;Francesco Marampon
;
Cinzia Marchese;Amalia Schiavetti;Francesca Megiorni.
2021

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Re-cently, we demonstrated the overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) in RMS tumour biopsies and cell lines compared to normal skeletal muscle. Radiotherapy may often fail due to the abnormal expression of some molecules able to drive resistance mechanisms. The aim of this study was to analyse the involvement of DNMT3A and DNMT3B in radioresistance in RMS. RNA interference experiments against DNMT3A/3B were performed in embryonal RMS cells, upon ionizing radiation (IR) exposure and the effects of the combined treatment on RMS cells were analysed. DNMT3A and DNMT3B knocking down increased the sensitivity of RMS cells to IR, as indicated by the drastic decrease of colony formation ability. In-terestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular se-nescence program by up-regulating p16 and p21, whilst DNMT3B depletion induces significant DNA damage and impairs the DNA repair machinery (ATM, DNA-PKcs and Rad51 reduction). Our findings demonstrate for the first time that DNMT3A and DNMT3B overexpression may contribute to radiotherapy failure, and their inhibition might be a promising radiosensitizing strategy, mainly in the treatment of patients with metastatic or recurrent RMS tumours. ©
differentiation therapies; DNA damage; DNMT3A; DNMT3B; radiotherapy; rhabdomyosarcoma; RNA inter-ference; senescence; target therapies
01 Pubblicazione su rivista::01a Articolo in rivista
Dnmt3a and dnmt3b targeting as an effective radiosensitizing strategy in embryonal rhabdomyosarcoma / Camero, Simona; Vitali, Giulia; Pontecorvi, Paola; Ceccarelli, Simona; Anastasiadou, Eleni; Cicchetti, Francesca; Flex, Elisabetta; Pomella, Silvia; Cassandri, Matteo; Rota, Rossella; Marampon, Francesco; Marchese, Cinzia; Schiavetti, Amalia; Megiorni, Francesca. - In: CELLS. - ISSN 2073-4409. - 10:11(2021). [10.3390/cells10112956]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1584546
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