| Title: |
HDAC3 genetic and pharmacologic inhibition radiosensitizes fusion positive rhabdomyosarcoma by promoting DNA double-strand breaks |
| Authors: |
Cassandri M; Porrazzo A; Pomella S; Noce B; Zwergel C; Aiello FA; Vulcano F; Milazzo L; Camero S; Pajalunga D; Spada M; Manzi V; Gravina GL; Codenotti S; Piccione M; Tomaciello M; Signore M; Barillari G; Marchese C; Fanzani A; De Angelis B; Quintarelli C; Vakoc CR; Chen EY; Megiorni F; Locatelli F; Valente S; Mai A; Rota R; Marampon F. |
| Contributors: |
Cassandri, M; Porrazzo, A; Pomella, S; Noce, B; Zwergel, C; Aiello, F; Vulcano, F; Milazzo, L; Camero, S; Pajalunga, D; Spada, M; Manzi, V; Gravina, G; Codenotti, S; Piccione, M; Tomaciello, M; Signore, M; Barillari, G; Marchese, C; Fanzani, A; De Angelis, B; Quintarelli, C; Vakoc, C; Chen, E; Megiorni, F; Locatelli, F; Valente, S; Mai, A; Rota, R; Marampon, F |
| Publication Year: |
2024 |
| Collection: |
Universitá degli Studi di Roma "Tor Vergata": ART - Archivio Istituzionale della Ricerca |
| Subject Terms: |
Settore MED/06; Settore MEDS-02/B - Patologia clinica |
| Description: |
radiotherapy (RT) plays a critical role in the management of rhabdomyosarcoma (RMS), the prevalent soft tissue sarcoma in childhood. the high risk PAX3-FOXO1 fusion-positive subtype (FP-RMS) is often resistant to RT. we have recently demonstrated that inhibition of class-I histone deacetylases (HDACs) radiosensitizes FP-RMS both in vitro and in vivo. however, HDAC inhibitors exhibited limited success on solid tumors in human clinical trials, at least in part due to the presence of off-target effects. hence, identifying specific HDAC isoforms that can be targeted to radiosensitize FP-RMS is imperative. we, here, found that only HDAC3 silencing, among all class-I HDACs screened by siRNA, radiosensitizes FP-RMS cells by inhibiting colony formation. thus, we dissected the effects of HDAC3 depletion using CRISPR/Cas9-dependent HDAC3 knock-out (KO) in FP-RMS cells, which resulted in endoplasmatic reticulum stress activation, ERK inactivation, PARP1- and caspase-dependent apoptosis and reduced stemness when combined with irradiation compared to single treatments. HDAC3 loss-of-function increased DNA damage in irradiated cells augmenting H2AX phosphorylation and DNA double-strand breaks (DSBs) and counteracting irradiation-dependent activation of ATM and DNA-Pkcs as well as Rad51 protein induction. moreover, HDAC3 depletion hampers FP-RMS tumor growth in vivo and maximally inhibits the growth of irradiated tumors compared to single approaches. we, then, developed a new HDAC3 inhibitor, MC4448, which showed specific cell anti-tumor effects and mirrors the radiosensitizing effects of HDAC3 depletion in vitro synergizing with ERKs inhibition. overall, our findings dissect the pro-survival role of HDAC3 in FP-RMS and suggest HDAC3 genetic or pharmacologic inhibition as a new promising strategy to overcome radioresistance in this tumor. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/wos/WOS:001284933200001; journal:CELL DEATH DISCOVERY; https://hdl.handle.net/2108/379444 |
| Availability: |
https://hdl.handle.net/2108/379444 |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.D48B0941 |
| Database: |
BASE |