title: Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.
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.
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Coni
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
authors.forename: Anna Barbara
authors.initials: AB
authors.lastname: Mancuso
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Roma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Magno
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Roma, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Sdruscia
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Manni
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
authors.forename: Silvia Maria
authors.initials: SM
authors.lastname: Serrao
authors.affiliation: Department of Drug chemistry and Technologies, SAPIENZA University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Spiombi
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Roma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bufalieri
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Roma, Italy.
authors.forename: Marialaura
authors.initials: M
authors.lastname: Petroni
authors.affiliation: Department of Cell Biology, Nencki Institute of Experimental Biology, 02-093, Warszawa, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kusio-Kobialka
authors.affiliation: Department of Experimental Medicine, SAPIENZA, University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.affiliation: Department of Experimental Medicine, SAPIENZA, University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.|Neuromed Institute, Pozzilli, 86077, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Capalbo
authors.affiliation: Department of Drug chemistry and Technologies, SAPIENZA University of Rome, P.le A. Moro 5, 00185, Rome, Italy.|Pasteur Lab, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Department of Cell Biology, Nencki Institute of Experimental Biology, 02-093, Warszawa, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Niewiadomski
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.|Pasteur Lab, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: Department of Molecular Medicine, SAPIENZA Unversity of Rome, Viale Regina Elena 291, 00161, Rome, Italy.|Pasteur Lab, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Canettieri
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C498520:Gli1 protein, mouse; D025521:Tumor Suppressor Proteins; D000071676:Zinc Finger Protein GLI1; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2