Glioblastoma invasion is controlled by parkin via a presenilin-dependent transcriptional control of N-cadherin

Glioblastoma (GBM) is a highly invasive uncurable cancer characterized by a poor prognosis. Parkin is a E3-ligase and transcription factor protein that has emerged as a tumor suppressor in various cancers including GBM via control of proliferation, cell metabolism and invasion. However, the contribution of its ligase and transcription factor function in invasion remained unknown. We examined, in a GBM context, the impact of parkin in the control of N-cadherin, a well characterized invasion player.By means of a bioinformatic analysis of open-source data, we established that parkin and N-cadherin mRNA levels are inversely expressed in IDH-wild-type and IDH-mutant gliomas suggesting a possible functional interplay between these proteins in GBM. Of importance, we show that parkin expression is associated with a better glioma prognosis.We demonstrate that parkin controls both individual and collective migration or invasion of U87 GBM cells and that this phenotype is associated with N-cadherin transcriptional regulation. Thus, parkin downregulates N-cadherin protein, promoter activity and mRNA levels. We also show that this transcriptional regulation is indirect and mediated by presenilins 1 and 2, which are key components of the γ-secretase complex implicated in the cleavage of substrates including N-cadherin. However, parkin-associated control of Ncad appears independent of presenilins-associated catalytic activity. Finally, we validated this signaling cascade in GBM patient-derived cell lines and showed that parkin E3-ligase activity also contributes to N-cadherin regulation.In brief, our study demonstrates that parkin controls invasion in GBM and highlights an intermediate role of presenilins in GBM spreading via N-cadherin regulation.