Yes-Associated Protein Nuclear Translocation Is Regulated by Epidermal Growth Factor Receptor Activation Through Phosphatase and Tensin Homolog/AKT Axis in Glioblastomas

Abstract

Gliomas are the most common and lethal primary brain tumors in adults. Glioblastomas, the most frequent and aggressive form of gliomas, represent a therapeutic challenge as no curative treatment exists to date, and the prognosis remains extremely poor. Recently, the transcriptional cofactors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) belonging to the Hippo pathway have emerged as a major determinant of malignancy in solid tumors, including gliomas. However, the mechanisms involved in its regulation, particularly in brain tumors, remain ill-defined. In glioblastomas, EGFR represents one of the most altered oncogenes affected by chromosomal rearrangements, mutations, amplifications, and overexpression. In this study, we investigated the potential link between epidermal growth factor receptor (EGFR) and the transcriptional cofactors YAP and TAZ by in situ and in vitro approaches. We first studied their activation on tissue microarray, including 137 patients from different glioma molecular subtypes. We observed that YAP and TAZ nuclear location was highly associated with isocitrate dehydrogenase 1/2 (IDH1/2) wild-type glioblastomas and poor patient outcomes. Interestingly, we found an association between EGFR activation and YAP nuclear location in glioblastoma clinical samples, suggesting a link between these 2 markers contrary to its ortholog TAZ. We tested this hypothesis in patient-derived glioblastoma cultures by pharmacologic inhibition of EGFR using gefinitib. We showed an increase of S397-YAP phosphorylation associated with decreased AKT phosphorylation after EGFR inhibition in phosphatase and tensin homolog (PTEN) wild-type cultures, unlike PTEN-mutated cell lines. Finally, we used bpV(HOpic), a potent PTEN inhibitor, to mimic the effect of PTEN mutations. We found that the inhibition of PTEN was sufficient to revert back the effect induced by Gefitinib in PTEN-wild-type cultures. Altogether, to our knowledge, these results show for the first time the regulation of pS397-YAP by the EGFR-AKT axis in a PTEN-dependent manner.

Keywords: AKT; EGFR; PTEN; TAZ; YAP; glioblastomas.