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.

Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma / Coni, Sonia; Mancuso, ANNA BARBARA; Di Magno, L; Sdruscia, Giulia; Manni, Simona; Serrao, SILVIA MARIA; Rotili, Dante; Spiombi, Eleonora; Bufalieri, Francesca; Petroni, Marialaura; Kusio Kobialka, M; DE SMAELE, Enrico; Ferretti, Elisabetta; Capalbo, Carlo; Mai, Antonello; Niewiadomski, P; Screpanti, Isabella; DI MARCOTULLIO, Lucia; Canettieri, Gianluca. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - STAMPA. - 7:44079(2017), p. 44079. [10.1038/srep44079]

Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.

CONI, SONIA;MANCUSO, ANNA BARBARA;Di Magno, L;sdruscia, giulia;Manni, Simona;SERRAO, SILVIA MARIA;ROTILI, Dante;SPIOMBI, ELEONORA;BUFALIERI, FRANCESCA;PETRONI, MARIALAURA;DE SMAELE, Enrico;FERRETTI, ELISABETTA;CAPALBO, CARLO;MAI, Antonello;SCREPANTI, Isabella;DI MARCOTULLIO, LUCIA;CANETTIERI, Gianluca
2017

Abstract

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.
2017
.
01 Pubblicazione su rivista::01a Articolo in rivista
Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma / Coni, Sonia; Mancuso, ANNA BARBARA; Di Magno, L; Sdruscia, Giulia; Manni, Simona; Serrao, SILVIA MARIA; Rotili, Dante; Spiombi, Eleonora; Bufalieri, Francesca; Petroni, Marialaura; Kusio Kobialka, M; DE SMAELE, Enrico; Ferretti, Elisabetta; Capalbo, Carlo; Mai, Antonello; Niewiadomski, P; Screpanti, Isabella; DI MARCOTULLIO, Lucia; Canettieri, Gianluca. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - STAMPA. - 7:44079(2017), p. 44079. [10.1038/srep44079]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/946157
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