HECTD3 regulates the tumourigenesis of glioblastoma by polyubiquitinating PARP1 and activating EGFR signalling pathway

Menée à l'aide de lignées cellulaires de glioblastome et de modèles murins, cette étude met en évidence un mécanisme par lequel la ligase HECTD3 régule la tumorigenèse via la poly-ubiquitination de la polymérase PARP1 et l'activation de la voie de signalisation du récepteur EGFR

Résumé en anglais

Background : The E3 ubiquitin ligase HECTD3 is a homologue of the E6-related protein carboxyl terminus, which plays a crucial role in biological processes and tumourigenesis. However, the functional characterisation of HECTD3 in glioblastoma is still elusive.

Methods : Determination of the functional role of HECTD3 in glioblastoma was made by a combination of HECTD3 molecular pattern analysis from human glioblastoma databases and subcutaneous and in situ injections of tumours in mice models.

Results : This study reports that the DOC domain of HECTD3 interacts with the DNA binding domain of PARP1, and HECTD3 mediated the K63-linked polyubiquitination of PARP1 and stabilised the latter expression. Moreover, the Cysteine (Cys) 823 (ubiquitin-binding site) mutation of HECTD3 significantly reduced PARP1 polyubiquitination and HECTD3 was involved in the recruitment of ubiquitin-related molecules to PARP1 ubiquitin-binding sites (Lysines 209 and 221, respectively). Lastly, activation of EGFR-mediated signalling pathways by HECTD3 regulates PARP1 polyubiquitination.

Conclusion : Our results unveil the potential role of HECTD3 in glioblastoma and strongly preconise further investigation and consider HECTD3 as a promising therapeutic marker for glioblastoma treatment.