Cassandri, Matteo, Porrazzo, Antonella, Pomella, Silvia, Noce, Beatrice, Zwergel, Clemens, Aiello, Francesca Antonella, Vulcano, Francesca, Milazzo, Luisa, Camero, Simona, Pajalunga, Deborah, Spada, Massimo, Manzi, Valeria, Gravina, Giovanni Luca, Codenotti, Silvia, Piccione, Michela, Tomaciello, Miriam, Signore, Michele, Barillari, Giovanni, Marchese, Cinzia, Fanzani, Alessandro, De Angelis, Biagio, Quintarelli, Concetta, Vakoc, Christopher R, Chen, Eleanor Y, Megiorni, Francesca, Locatelli, Franco, Valente, Sergio, Mai, Antonello, Rota, Rossella, Marampon, Francesco (August 2024) HDAC3 genetic and pharmacologic inhibition radiosensitizes fusion positive rhabdomyosarcoma by promoting DNA double-strand breaks. Cell Death Discovery, 10 (1). p. 351. ISSN 2058-7716 (Public Dataset)
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Abstract
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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > sarcoma diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Vakoc lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 6 August 2024 |
| Date Deposited: | 12 Aug 2024 17:13 |
| Last Modified: | 12 Aug 2024 17:13 |
| PMCID: | PMC11303816 |
| Related URLs: | |
| Dataset ID: |
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| URI: | https://repository.cshl.edu/id/eprint/41632 |
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