Ewing sarcoma (EWS), a highly aggressive pediatric tumor, is driven by EWS-FLI1, an oncogenic transcription factor that remodels the tumor genetic landscape. Epigenetic mechanisms play a pivotal role in EWS pathogenesis, and the therapeutic value of compounds targeting epigenetic pathways is being identified in preclinical models. Here we showed that modulation of CD99, a cell surface molecule highly expressed in EWS cells, may alter transcriptional dysregulation in EWS through control of the zyxin-Gli1 axis. Zyxin is transcriptionally repressed, but Gli1 expression is maintained by EWS-FLI1. We demonstrated that targeting CD99 with antibodies, including the human diabody C7, or genetically inhibiting CD99 is sufficient to increase zyxin expression and induce its dynamic nuclear accumulation. Nuclear zyxin functionally affects Gli1, inhibiting targets such as NKX2-2, cyclin D1, and PTCH1 and upregulating GAS1, a tumor suppressor protein negatively regulated by Shh/Gli1 signaling We used a battery of functional assays to demonstrate: a) the relationship between CD99/zyxin and tumor cell growth/migration and; b) how CD99 deprivation from the EWS cell surface is sufficient to specifically affect the expression of some crucial EWS-FLI1 targets, both in vitro and in vivo, even in the presence of EWS-FLI1This work reveals that the CD99/zyxin/Gli1 axis is promising therapeutic target for reducing EWS malignancy.

Targeting CD99 compromises the oncogenic effects of the chimera EWS-FLI1 by inducing re-expression of zyxin and inhibition of Gli1 activity

Balestra, Tommaso;Manara, Maria Cristina;Laginestra, Maria Antonella;Pasello, Michela;De Feo, Alessandra;Landuzzi, Lorena;Lollini, Pier-Luigi;Donati, Davide Maria;Scotlandi, Katia
2022

Abstract

Ewing sarcoma (EWS), a highly aggressive pediatric tumor, is driven by EWS-FLI1, an oncogenic transcription factor that remodels the tumor genetic landscape. Epigenetic mechanisms play a pivotal role in EWS pathogenesis, and the therapeutic value of compounds targeting epigenetic pathways is being identified in preclinical models. Here we showed that modulation of CD99, a cell surface molecule highly expressed in EWS cells, may alter transcriptional dysregulation in EWS through control of the zyxin-Gli1 axis. Zyxin is transcriptionally repressed, but Gli1 expression is maintained by EWS-FLI1. We demonstrated that targeting CD99 with antibodies, including the human diabody C7, or genetically inhibiting CD99 is sufficient to increase zyxin expression and induce its dynamic nuclear accumulation. Nuclear zyxin functionally affects Gli1, inhibiting targets such as NKX2-2, cyclin D1, and PTCH1 and upregulating GAS1, a tumor suppressor protein negatively regulated by Shh/Gli1 signaling We used a battery of functional assays to demonstrate: a) the relationship between CD99/zyxin and tumor cell growth/migration and; b) how CD99 deprivation from the EWS cell surface is sufficient to specifically affect the expression of some crucial EWS-FLI1 targets, both in vitro and in vivo, even in the presence of EWS-FLI1This work reveals that the CD99/zyxin/Gli1 axis is promising therapeutic target for reducing EWS malignancy.
2022
Balestra, Tommaso; Manara, Maria Cristina; Laginestra, Maria Antonella; Pasello, Michela; De Feo, Alessandra; Bassi, Cristian; Guerzoni, Clara; Landuzzi, Lorena; Lollini, Pier-Luigi; Donati, Davide Maria; Negrini, Massimo; Magnani, Mauro; Scotlandi, Katia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/847653
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