Corrigendum: Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma
| Autor: | Gianluca Canettieri, Elisabetta Ferretti, Anna Barbara Mancuso, Eleonora Spiombi, Marialaura Petroni, Pawel Niewiadomski, Lucia Di Marcotullio, Dante Rotili, Francesca Bufalieri, Sonia Coni, Simona Manni, Laura Di Magno, Monika Kusio-Kobialka, Giulia Sdruscia, Silvia Maria Serrao, Carlo Capalbo, Isabella Screpanti, Enrico De Smaele, Antonello Mai |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
animal structures Histone Deacetylase 2 Histone Deacetylase 1 Mice Transgenic Zinc Finger Protein GLI1 Article 03 medical and health sciences Mice GLI1 Cell Line Tumor medicine Animals Medulloblastoma Multidisciplinary biology Tumor Suppressor Proteins Neoplasms Experimental medicine.disease Corrigenda HDAC1 030104 developmental biology Acetylation embryonic structures biology.protein Cancer research Experimental biology |
| Zdroj: | Scientific Reports |
| Popis: | SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB. |
| Databáze: | OpenAIRE |
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