DYT8 drives lung adenocarcinoma through EGFR-mediated PSMC6 recruitment and uncharacterized phosphorylation at Ser 306 and 525 of c-Src.

Abstract

Lung adenocarcinoma (LUAD) is a multi-kinase hyperactivation-driven malignancy. Targeted therapies are effective but have limited application, primarily due to a small eligible patient population and the development of drug resistance. Analysis of TCGA and tissue microarray show that Dystonia 8 (DYT8) is specially highly expressed in more than 70% of LUAD patients. Furthermore, increased DYT8 expression is positively associated with tumor malignancy and negatively associated with survival. Using the Dyt8 knock-in (cKras^LSL-G12D/+p53^R172H/+-Dyt8-KI) and knockout (cKras^LSL-G12D/+p53^R172H/+-Dyt8-KO) transgenic mice, we identify DYT8 as key activator that accelerates the initiation and progression of LUAD. Mechanistically, EGFR-mediated phosphorylation of DYT8 at Y120 reinforces its stability by increasing its interaction with PSMC6, a protein that is highly expressed in LUAD and associated with an unfavorable prognosis. DYT8 drives LUAD malignant transformation by activating Src. Although Y419 phosphorylation is a recognized key event in Src-driven LUAD, our study identifies novel phosphorylation sties at S306 and S525 that are activated by DYT8, which these novel sites being more critical for DYT8-driven malignant transformation than Y419 phosphorylation. Furthermore, the knockdown of Dyt8 rescues EGFR-triggered carcinogenesis and resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). These findings reveal that DYT8 drives LUAD via a previously unreported Src activation mechanism and identify EGFR-DYT8-PSMC6 axis as the key determinant of high DYT8 level, thereby conferring a novel therapeutic strategy for wider LUAD patients, including those with EGFR-TKIs resistant.