Neurokinin-1 regulates progression of triple negative breast cancer by enhancing G3BP2 SUMOylation.

Neurokinin-1 (NK-1) is a G protein-coupled receptor for substance P and plays important roles in regulating diverse physiological and pathological processes. Previous studies have shown that NK-1 can modulate cell apoptosis in various malignancies, including triple-negative breast cancer (TNBC). This study aims to investigate the role of GTPase-activating protein (SH3 domain)-binding protein 2 (G3BP2) SUMOylation in NK-1-regulated progression in TNBC. Co-immunoprecipitation coupled with mass spectrometry was used to identify NK-1-interacting proteins and validate G3BP2, followed by truncation mapping, immunohistochemistry, functional assays, and site-directed mutagenesis to define its binding region, clinical relevance, and SUMOylation sites in TNBC. G3BP2 was identified as an NK-1-binding protein and was overexpressed in TNBC, correlating with poor overall survival. G3BP2 SUMOylation could enhance protein stability, thereby promoting TNBC cell proliferation and inhibiting apoptosis. G3BP2 interacted with NK-1 to facilitate UBC9/SUMO1-mediated SUMOylation at K281. Our findings demonstrate that NK-1 contributes to TNBC progression by regulating G3BP2 SUMOylation, revealing a critical post-translational modification mechanism underlying TNBC pathogenesis and highlighting the NK-1/G3BP2 SUMOylation axis as a potential therapeutic target.