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.
| Original language | English |
|---|---|
| Article number | 44079 |
| Journal | Scientific Reports |
| Volume | 7 |
| DOIs | |
| Publication status | Published - Mar 9 2017 |
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Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma. / Coni, Sonia; Mancuso, Anna Barbara; Di Magno, Laura; Sdruscia, Giulia; Manni, Simona; Serrao, Silvia Maria; Rotili, Dante; Spiombi, Eleonora; Bufalieri, Francesca; Petroni, Marialaura; Kusio-Kobialka, Monika; De Smaele, Enrico; Ferretti, Elisabetta; Capalbo, Carlo; Mai, Antonello; Niewiadomski, Pawel; Screpanti, Isabella; Di Marcotullio, Lucia; Canettieri, Gianluca.
In: Scientific Reports, Vol. 7, 44079, 09.03.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma
AU - Coni, Sonia
AU - Mancuso, Anna Barbara
AU - Di Magno, Laura
AU - Sdruscia, Giulia
AU - Manni, Simona
AU - Serrao, Silvia Maria
AU - Rotili, Dante
AU - Spiombi, Eleonora
AU - Bufalieri, Francesca
AU - Petroni, Marialaura
AU - Kusio-Kobialka, Monika
AU - De Smaele, Enrico
AU - Ferretti, Elisabetta
AU - Capalbo, Carlo
AU - Mai, Antonello
AU - Niewiadomski, Pawel
AU - Screpanti, Isabella
AU - Di Marcotullio, Lucia
AU - Canettieri, Gianluca
PY - 2017/3/9
Y1 - 2017/3/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014895304&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014895304&partnerID=8YFLogxK
U2 - 10.1038/srep44079
DO - 10.1038/srep44079
M3 - Article
AN - SCOPUS:85014895304
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 44079
ER -