A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development
Menée in vitro, in silico et à l'aide de xénogreffes de glioblastomes sur des modèles murins, cette étude met en évidence l'intérêt, pour réduire le développement tumoral, d'un répresseur synthétique épigénétique obtenu en fusionnant le domaine KRAB de la protéine ZNF10 et/ou le domaine catalytique du complexe DNMT3A-DNMT3L avec la séquence complète ou tronquée de SOX2 (absence du domaine d'activation transcriptionnelle C-terminal)
Current therapies remain unsatisfactory in preventing the recurrence of glioblastoma multiforme (GBM), which leads to poor patient survival. By rational engineering of the transcription factor SOX2, a key promoter of GBM malignancy, together with the Kruppel-associated box and DNA methyltransferase3A/L catalytic domains, we generated a synthetic repressor named SOX2 epigenetic silencer (SES), which induces the transcriptional silencing of its original targets. By doing so, SES kills both glioma cell lines and patient-derived cancer stem cells in vitro and in vivo. SES expression, through local viral delivery in mouse xenografts, induces strong regression of human tumors and survival rescue. Conversely, SES is not harmful to neurons and glia, also thanks to a minimal promoter that restricts its expression in mitotically active cells, rarely present in the brain parenchyma. Collectively, SES produces a significant silencing of a large fraction of the SOX2 transcriptional network, achieving high levels of efficacy in repressing aggressive brain tumors. The SOX2 epigenetic silencer (SES) is a synthetic GBM inhibitor factor that represses the SOX2 oncogenic transcriptional network.
Science Advances 2022