Nuclear sortilin controls genes involved in oncogenic pathways in lung adenocarcinoma

Abstract Sortilin, a glycoprotein belonging to the Vps10 family, is mainly recognized for its contribution to protein sorting. Its dichotomous role in oncology, between tumor promotion and suppression, remains highly controversial. Our present study reveals a novel mechanism relying on the nuclear localization of sortilin, acting on transcription, chromatin reorganization and DNA repair. Its role in limiting tumor progression of lung adenocarcinoma cell lines was confirmed with sustained EGFR proliferative signaling. Furthermore, we report that sortilin overexpression limits the growth of NCI-H1975 and NCI-H3255 cell lines, regulating gene expression but also indirectly altering oncogenic pathways such as MTOR and AKT. Through its transcriptional action, sortilin interacts directly with proteins central to DNA repair mechanisms and chromatin reorganization. Finally, our findings reshape the traditional view of sortilin, suggesting implications not restricted to its simple protein transport, which contributes to explain its heterogeneous roles in different tumors. These insights also position sortilin as a promising candidate to engineer innovative therapeutics in lung adenocarcinoma.