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. 2024 Mar 21;134(10):e174587. doi: 10.1172/JCI174587

Figure 6. AARS1 promotes gastric cancer overgrowth via YAP-TEAD lactylation.

Figure 6

(A) Heatmap of differentially expressed genes in AARS1-knockdown cells upon lactate treatment. RNA-Seq was performed to evaluate the transcriptomics of AARS1 siRNA–transfected HGC27 cells cultured in glucose-free medium with lactate for 12 hours. (B) GSEA of Hippo signature genes in lactate-treated HGC27 cells. Normalized enrichment score and FDR are shown. (C) mRNA levels of CTGF and CYR61 in AARS1-knockout cells upon lactate treatment (n = 3). Glc, glucose; Lac, lactate. Data are presented as mean ± SD. (D) Lactylation levels of YAP and TEAD1 in AARS1-knockout cells upon lactate treatment. (E) Top: Immunofluorescence images of YAP localization in scramble control and AARS1-knockdown cells upon lactate treatment for 12 hours. Bottom: Quantification of YAP signal intensity (n = 3). N, nuclear localization; C, cytosolic localization. Data are presented as mean ± SD. Scale bar: 5 μm. (F) Percentage of EdU+ cells in AARS1-knockdown cells treated with lactate for 12 hours (n = 3). Data are presented as mean ± SD. (G) Cell growth curves of scramble control and AARS1-knockdown cells upon lactate treatment (n = 3). Data are presented as mean ± SD. (H) Rescue assay showing cell growth of AARS1-knockdown cells after enforced expression of YAP5A and TEAD1 upon lactate treatment (n = 3). YAP5A: S61A, S109A, S127A, S164A, S397A. Data are presented as mean ± SD. (I) Cell growth curves of HA-AARS1–overexpressing cells after YAP and TEAD1 depletion upon lactate treatment (n = 3). Data are presented as mean ± SD. (J) Xenograft murine GC model after subcutaneous injection with HGC27 cells transfected with indicated plasmids. Tumor growth curves (left) and representative tumor images (right) are shown (n = 6). (K) Orthotopic murine GC model after injection with HGC27 cells transfected with indicated plasmids. Left: Representative images. Right: Measurement of tumor area (n = 10). Unpaired 2-tailed Student’s t test (C, E, F, and K); 1-way ANOVA (G–J).