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      Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

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          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.

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          Improved protein-ligand docking using GOLD.

          Marcel Verdonk, Jason Cole, Michael J Hartshorn … (2003)
          The Chemscore function was implemented as a scoring function for the protein-ligand docking program GOLD, and its performance compared to the original Goldscore function and two consensus docking protocols, "Goldscore-CS" and "Chemscore-GS," in terms of docking accuracy, prediction of binding affinities, and speed. In the "Goldscore-CS" protocol, dockings produced with the Goldscore function are scored and ranked with the Chemscore function; in the "Chemscore-GS" protocol, dockings produced with the Chemscore function are scored and ranked with the Goldscore function. Comparisons were made for a "clean" set of 224 protein-ligand complexes, and for two subsets of this set, one for which the ligands are "drug-like," the other for which they are "fragment-like." For "drug-like" and "fragment-like" ligands, the docking accuracies obtained with Chemscore and Goldscore functions are similar. For larger ligands, Goldscore gives superior results. Docking with the Chemscore function is up to three times faster than docking with the Goldscore function. Both combined docking protocols give significant improvements in docking accuracy over the use of the Goldscore or Chemscore function alone. "Goldscore-CS" gives success rates of up to 81% (top-ranked GOLD solution within 2.0 A of the experimental binding mode) for the "clean list," but at the cost of long search times. For most virtual screening applications, "Chemscore-GS" seems optimal; search settings that give docking speeds of around 0.25-1.3 min/compound have success rates of about 78% for "drug-like" compounds and 85% for "fragment-like" compounds. In terms of producing binding energy estimates, the Goldscore function appears to perform better than the Chemscore function and the two consensus protocols, particularly for faster search settings. Even at docking speeds of around 1-2 min/compound, the Goldscore function predicts binding energies with a standard deviation of approximately 10.5 kJ/mol. Copyright 2003 Wiley-Liss, Inc.
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            HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity.

            Virginie Clement, Pilar Cartón Sánchez, Nicolas de Tribolet … (2007)
            Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.
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              Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists.

              Matthias Lauth, Åsa Bergström, Takashi Shimokawa … (2007)
              The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EMBO J
                Journal ID (iso-abbrev): EMBO J
                Journal ID (publisher-id): embj
                Title: The EMBO Journal
                Publisher: Blackwell Publishing Ltd (Oxford, UK )
                ISSN (Print): 0261-4189
                ISSN (Electronic): 1460-2075
                Publication date (Print): 14 January 2015
                Publication date (Electronic): 04 December 2014
                Volume: 34
                Issue: 2
                Pages: 200-217
                Affiliations
                [1 ]Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia Rome, Italy
                [2 ]Department of Molecular Medicine, University La Sapienza Rome, Italy
                [3 ]Dipartimento di Chimica e Tecnologie del Farmaco, University La Sapienza Rome, Italy
                [4 ]Department of Chemistry and Industrial Chemistry, University of Pisa Pisa, Italy
                [5 ]Department of Experimental Medicine, University La Sapienza Rome, Italy
                [6 ]Department of Biotechnology, Chemistry and Pharmacy, University of Siena Siena, Italy
                [7 ]Sbarro Institute for Cancer Research and Molecular Medicine, Temple University Philadelphia, PA, USA
                [8 ]Istituto Pasteur, Fondazione Cenci-Bolognetti - University La Sapienza Rome, Italy
                [9 ]IRCCS Neuromed Pozzilli, Italy
                Author notes
                *Corresponding author. Tel: +39 649255657; Fax: +39 649255660; E-mail: lucia.dimarcotullio@ 123456uniroma1.it
                **Corresponding author. Tel: +39 649255129; Fax: +39 649255660; E-mail: alberto.gulino@ 123456uniroma1.it
                ***Corresponding author. Tel: +39 649912781; E-mail: bruno.botta@ 123456uniroma1.it
                [†]

                These authors contributed equally to this work

                Subject Categories Cancer; Chemical Biology; Structural Biology

                Article
                DOI: 10.15252/embj.201489213
                PMC ID: 4298015
                PubMed ID: 25476449
                SO-VID: d7f4b4af-51d9-48bf-a9bd-010826db7abb
                Copyright © © 2014 The Authors. Published under the terms of CC BY NC ND 4.0 license
                License:

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 10 June 2014
                Date revision received : 04 November 2014
                Date accepted : 12 November 2014
                Categories
                Subject: Articles

                ScienceOpen disciplines: Molecular biology
                Keywords: cancer,gli inhibitors,gli1–dna interaction,hedgehog
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: cancer, gli inhibitors, gli1–dna interaction, hedgehog

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