Abstract
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.
Highlights
Licensee MDPI, Basel, Switzerland.Rhabdomyosarcoma (RMS) represents about 3–5% of malignant solid tumours in the paediatric population and is the most common soft tissue sarcoma in children
Since we recently demonstrated the up-regulation of both DNA methyltransferase 3A (DNMT3A) and DNMT3B
The comparison between si-DNMT3B/4 Gy vs. si-DNMT3B or vs. si-NC/4 Gy was not significant, indicating that DNMT3B knocking down and radiotherapy affect cell migration but do not act synergistically on its inhibition. These results suggest that DNMT3A and DNMT3B depletion potentiates the cytostatic effect induced by ionizing radiation (IR) on RD cells in two different ways: si-DNMT3A activity is independent of DNA damage, whilst si-DNMT3B exerts its effects by blocking the DNA
Summary
Licensee MDPI, Basel, Switzerland.Rhabdomyosarcoma (RMS) represents about 3–5% of malignant solid tumours in the paediatric population and is the most common soft tissue sarcoma in children. RMS originates from myogenic precursors, which have lost the control in cell growth and differentiation [1] and is characterized by a high grade of malignancy, local invasiveness, and a marked propensity to metastasize [2]. ARMS tumours are more frequent in children and adolescents and are characterized by a more aggressive course, with metastases already diffuse at diagnosis and a poor prognosis, whilst ERMSs arise especially in infants and young children and are generally correlated with a better outcome [1,3]. Understanding all the factors and the molecular pathways involved in the radioresistance mechanisms is crucial for the development of innovative therapies, more effective and less toxic for patients with RMS tumours
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
