MST4 plays dual roles in lung adenocarcinoma by regulating homeostasis of wild-type and mutant p53 protein.

Mutations are highly prevalent in the TP53 tumor suppressor gene, which encodes p53, in lung adenocarcinoma (LUAD). However, targeted therapies centered on p53 mutations remain challenging. Here, we found MST4 highly expressed in LUAD and linked to patient survival. Functional assays using CRISPR-generated MST4-knockout LUAD cell lines revealed context-dependent dual roles of MST4: tumor-suppressive in wild-type p53 (wtp53) cells (inhibiting proliferation, colony formation, migration) and oncogenic in gain-of-function (GOF) p53 cells. Mechanistically, MST4 directly interacts with p53, competing with MDM2 to prevent K48-linked ubiquitination and degradation of both wtp53 and GOF-mutant p53, which explains cell-context-dependent phenotypes of MST4 suppression. Preclinically, targeting MST4 significantly repressed tumor formation of xenograft model with GOF-mutant p53. Collectively, our findings identify MST4 as a context-dependent regulator of LUAD, whose function is dictated by p53 mutation status. MST4 stabilizes p53 via a novel MDM2-competitive, kinase-independent mechanism, and targeting MST4 represents a promising therapeutic strategy for GOF-mutant p53-driven LUAD.