Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype that lacks targeted therapies, highlighting the urgent need for novel treatment strategies. Clinical evidence shows that TNBC patients with metabolic dysregulation—such as obesity or diabetes, often accompanied by hyperglycemia—exhibit worse prognoses, underscoring the role of metabolic stress in TNBC progression. At the cellular level, nutrients in the tumor microenvironment influence cancer progression by regulating cancer cell metabolism and ultimately affecting host–cancer interactions. Our previous work demonstrated that high extracellular glucose modulates cytoskeletal remodeling by regulating F-actin assembly and non-muscle myosin activity via the cAMP–RhoA–ROCK pathway in TNBC cells. We further found that pharmacologic inhibition of glucose transporter 3 (GLUT3) reduces glycolysis, leading to activation of AMPK and PKA signaling pathways and suppression of actin dynamics. Treatment with verteporfin, a YAP–TEAD inhibitor, decreased VASP expression, suggesting that VASP is a potential novel target gene of YAP–TEAD. To test our hypothesis that VASP is a novel YAP–TEAD target gene, we analyzed public ChIP-seq data and identified four potential YAP–TEAD co-binding sites in the enhancer regions of VASP. Motif scanning confirmed TEAD motifs in these regions, and luciferase reporter assays validated their enhancer activity. TEAD isoform-specific siRNA experiments further revealed distinct contributions of TEAD isoforms to this regulatory axis. Additionally, RNA-seq datasets across breast cancer cell lines showed that VASP expression is upregulated under high-glucose conditions. This was experimentally validated by measuring endogenous VASP expression levels and luciferase activity in cells treated with varying glucose concentrations, as well as with G3iA, a selective GLUT3 inhibitor. Taken together, our work demonstrates that targeting glucose uptake attenuates hyperglycemia-induced pro-metastatic signaling at the transcriptional level, suggesting a mechanism by which cancer cells adapt to nutrient availability in the tumor microenvironment. Citation Format: Wonkyung Lee, Seeun Oh, Aadil Qadir. Bhat, Tae-Hyung Kim. Identification of VASP as a glucose-sensitive YAP-TEAD target gene in a human triple-negative breast cancer cell line abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85 (23Suppl): Abstract nr B020.
Oh et al. (Thu,) studied this question.