title: Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors.
abstract: Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling.
authors.affiliation: Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Infante
authors.affiliation: Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Alfonsi
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, University La Sapienza, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ghirga
authors.affiliation: Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Aiello
authors.affiliation: Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Toscano
authors.affiliation: Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Ingallina
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Siler
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Cucchi
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Po
authors.affiliation: Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Miele
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: D'Amico
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Canettieri
authors.affiliation: Department of Experimental Medicine, University La Sapienza, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.affiliation: Department of Experimental Medicine, University La Sapienza, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Uccello Barretta
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, University La Sapienza, Rome, Italy lucia.dimarcotullio@uniroma1.it alberto.gulino@uniroma1.it bruno.botta@uniroma1.it.
authors.forename: Bruno
authors.initials: B
authors.lastname: Botta
authors.affiliation: Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy Department of Molecular Medicine, University La Sapienza, Rome, Italy Istituto Pasteur, Fondazione Cenci-Bolognetti - University La Sapienza, Rome, Italy IRCCS Neuromed, Pozzilli, Italy lucia.dimarcotullio@uniroma1.it alberto.gulino@uniroma1.it bruno.botta@uniroma1.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy lucia.dimarcotullio@uniroma1.it alberto.gulino@uniroma1.it bruno.botta@uniroma1.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007529:Isoflavones / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D007529:Isoflavones; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1; D004247:DNA
keywords: Gli inhibitors; Gli1–DNA interaction; Hedgehog; cancer