ELENA LORICCHIO

Dottoressa di ricerca

ciclo: XXXIV



Titolo della tesi: Deciphering the role of the transcription factor SALL4A in the regulation of the Hedgehog pathway and in the pathogenesis of medulloblastoma

The Hedgehog (Hh) pathway is essential in embryonic development and its aberrant activation is responsible for the onset of several tumors. Hh signalling activation is promoted by the binding of Hh extracellular ligands to the Patched inhibitor receptor (PTCH1). This interaction determines the release of the inhibitory effect exerted by PTCH1 on the activator co-receptor Smoothened (SMO), thus triggering the signal transduction cascade that culminates with the activation of zinc-finger transcription factors of the GLI family, responsible for the expression of target genes involved in the most important biological processes (i.e., proliferation, survival, differentiation, and stemness). Given the relevance of Hh signalling in tumorigenesis, the study of the molecular mechanisms as well as the identification of new key players that control its activity represent an area of great interest in tumor biology. To address this aim, my research has been focused on the characterization of novel interactors of the known Hh negative regulator and tumor suppressor RENKCTD11. Starting from the mass spectrometry analysis, we identified different potential RENKCTD11 interactors and among them we focused our attention on SALL4A. SALL4A belongs to the 4-member Spalt-Like protein family (SALL1-4), first identified in Drosophila Melanogaster. SALL4A is a zinc-finger transcription factor that plays a fundamental role in maintaining pluripotency and in the self-renewal of embryonic stem cells (ESCs). SALL4A regulates many genes, thus making this transcription factor essential for the regulation of numerous signalling pathways. SALL4A is highly expressed in the earliest stages of development, and its expression progressively decreases until it is almost completely inhibited in adults. The over expression of SALL4A has been found in several tumor such as brain, breast, lung, and colon-rectal cancers. We found that SALL4A is a substrate of RENKCTD11, which promotes its poly-ubiquitylation and proteasome-dependent degradation. We demonstrated that SALL4A acts as a positive regulator of the Hh pathway enhancing GLI1 transcriptional activity. Specifically, we show that SALL4A and HDAC1 form a complex with GLI1 increasing the binding affinity of the complex and favoring the recruitment of HDAC1 to GLI1. This event leads to GLI1 deacetylation and its activation (Canettieri et al. 2010). Of note, we observed that genetic depletion of SALL4A strongly reduces Hh-dependent MB cells growth in vitro and impairs tumor formation in vivo. In conclusion, results obtained by my Ph.D. project unveil a novel molecular mechanism involved in Hh signaling control and contribute to elucidate the biology of Hh-dependent MB through the identification of SALL4A as a new player of Hh signalling. In this scenario, SALL4A stands as a potential target for the development of new and more effective therapies for Hh-dependent tumors care.

Produzione scientifica

11573/1692856 - 2024 - SALL4 is a CRL3^REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma
Lospinoso Severini, Ludovica; Loricchio, Elena; Navacci, Shirin; Basili, Irene; Alfonsi, Romina; Bernardi, Flavia; Moretti, Marta; Conenna, Marilisa; Cucinotta, Antonino; Coni, Sonia; Petroni, Marialaura; De Smaele, Enrico; Giannini, Giuseppe; Maroder, Marella; Canettieri, Gianluca; Mastronuzzi, Angela; Guardavaccaro, Daniele; Ayrault, Olivier; Infante, Paola; Bufalieri, Francesca; Di Marcotullio, Lucia - 01a Articolo in rivista
rivista: CELL DEATH AND DIFFERENTIATION (Nature Publishing Group:Brunel Road Houndmills, Basingstoke RG21 6XS United Kingdom:011 44 20 78334000, EMAIL: institutions@natureny.com, INTERNET: http://www.nature.com, Fax: 011 44 20 78434640) pp. - - issn: 1350-9047 - wos: WOS:001119029000002 (2) - scopus: 2-s2.0-85178929821 (2)

11573/1613665 - 2021 - Drug delivery systems for hedgehog inhibitors in the treatment of SHH-medulloblastoma
Caimano, M.; Lospinoso Severini, L.; Loricchio, E.; Infante, P.; Di Marcotullio, L. - 01g Articolo di rassegna (Review)
rivista: FRONTIERS IN CHEMISTRY (Lausanne : Frontiers Media S.A., 2013-) pp. - - issn: 2296-2646 - wos: WOS:000663813400001 (11) - scopus: 2-s2.0-85108348605 (10)

11573/1613699 - 2021 - A new smoothened antagonist bearing the purine scaffold shows antitumour activity in vitro and in vivo
Zarate, A. M.; Espinosa-Bustos, C.; Guerrero, S.; Fierro, A.; Oyarzun-Ampuero, F.; Quest, A. F. G.; Di Marcotullio, L.; Loricchio, E.; Caimano, M.; Calcaterra, A.; Gonzalez-Quiroz, M.; Aguirre, A.; Melendez, J.; Salas, C. O. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:000690546100001 (10) - scopus: 2-s2.0-85111760377 (10)

11573/1384478 - 2020 - The rna-binding ubiquitin ligase mex3a affects glioblastoma tumorigenesis by inducing ubiquitylation and degradation of rig-i
Bufalieri, F.; Caimano, M.; Severini, L. L.; Basili, I.; Paglia, F.; Sampirisi, L.; Loricchio, E.; Petroni, M.; Canettieri, G.; Santoro, A.; D'angelo, L.; Infante, P.; Di Marcotullio, L. - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 321- - issn: 2072-6694 - wos: WOS:000522477300067 (37) - scopus: 2-s2.0-85079068523 (40)

11573/1559760 - 2020 - Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold
Romeo, Isabella; Lospinoso Severini, Ludovica; Quaglio, Deborah; Basili, Irene; Ghirga, Francesca; Bufalieri, Francesca; Caimano, Miriam; Balducci, Silvia; Moretti, Marta; Loricchio, Elena; Maroder, Marella; Botta, Bruno; Mori, Mattia; Infante, Paola; Di Marcotullio, Lucia - 04f Poster
congresso: STRATAGEM COST CA17104: New diagnostic and therapeutic tools against multidrug resistant tumors (virtual meeting - online mode)
libro: Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold - ()

11573/1321077 - 2019 - A Smo/Gli multitarget hedgehog pathway inhibitor impairs tumor growth
Lospinoso Severini, Ludovica; Quaglio, Deborah; Basili, Irene; Ghirga, Francesca; Bufalieri, Francesca; Caimano, Miriam; Balducci, Silvia; Moretti, Marta; Romeo, Isabella; Loricchio, Elena; Maroder, Marella; Botta, Bruno; Mori, Mattia; Infante, Paola; Di Marcotullio, Lucia - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 1518-1534 - issn: 2072-6694 - wos: WOS:000498826000115 (36) - scopus: 2-s2.0-85073503434 (37)

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