DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, 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...

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Autores principales:	Simona Camero, Giulia Vitali, Paola Pontecorvi, Simona Ceccarelli, Eleni Anastasiadou, Francesca Cicchetti, Elisabetta Flex, Silvia Pomella, Matteo Cassandri, Rossella Rota, Francesco Marampon, Cinzia Marchese, Amalia Schiavetti, Francesca Megiorni
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	rhabdomyosarcoma DNMT3A DNMT3B radiotherapy target therapies RNA interference Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/664cd9295ee447589ec4efc14f072f15
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spelling	oai:doaj.org-article:664cd9295ee447589ec4efc14f072f152021-11-25T17:09:47ZDNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma10.3390/cells101129562073-4409https://doaj.org/article/664cd9295ee447589ec4efc14f072f152021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2956https://doaj.org/toc/2073-4409Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, 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. Interestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular senescence 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.Simona CameroGiulia VitaliPaola PontecorviSimona CeccarelliEleni AnastasiadouFrancesca CicchettiElisabetta FlexSilvia PomellaMatteo CassandriRossella RotaFrancesco MaramponCinzia MarcheseAmalia SchiavettiFrancesca MegiorniMDPI AGarticlerhabdomyosarcomaDNMT3ADNMT3Bradiotherapytarget therapiesRNA interferenceBiology (General)QH301-705.5ENCells, Vol 10, Iss 2956, p 2956 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	rhabdomyosarcoma DNMT3A DNMT3B radiotherapy target therapies RNA interference Biology (General) QH301-705.5
spellingShingle	rhabdomyosarcoma DNMT3A DNMT3B radiotherapy target therapies RNA interference Biology (General) QH301-705.5 Simona Camero Giulia Vitali Paola Pontecorvi Simona Ceccarelli Eleni Anastasiadou Francesca Cicchetti Elisabetta Flex Silvia Pomella Matteo Cassandri Rossella Rota Francesco Marampon Cinzia Marchese Amalia Schiavetti Francesca Megiorni DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma
description	Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, 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. Interestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular senescence 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.
format	article
author	Simona Camero Giulia Vitali Paola Pontecorvi Simona Ceccarelli Eleni Anastasiadou Francesca Cicchetti Elisabetta Flex Silvia Pomella Matteo Cassandri Rossella Rota Francesco Marampon Cinzia Marchese Amalia Schiavetti Francesca Megiorni
author_facet	Simona Camero Giulia Vitali Paola Pontecorvi Simona Ceccarelli Eleni Anastasiadou Francesca Cicchetti Elisabetta Flex Silvia Pomella Matteo Cassandri Rossella Rota Francesco Marampon Cinzia Marchese Amalia Schiavetti Francesca Megiorni
author_sort	Simona Camero
title	DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma
title_short	DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma
title_full	DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma
title_fullStr	DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma
title_full_unstemmed	DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma
title_sort	dnmt3a and dnmt3b targeting as an effective radiosensitizing strategy in embryonal rhabdomyosarcoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/664cd9295ee447589ec4efc14f072f15
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DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma

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