Journal: Communications Biology

Article Title: A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer

doi: 10.1038/s42003-025-08740-2

Figure Lengend Snippet: a Volcano diagram showing the number of differentially expressed genes in YAP1-replete (WT; control) compared to YAP1 −/− HCT116 cells. Dashed horizontal and vertical lines indicate significance thresholds (|FC | > 0.5, P < 0.05). A positive fold change means that the gene is upregulated by YAP1. Genes are colored in gray (non-significant), blue ( P -value significant), and red (both P -values and fold change are significant). All labeled genes exhibit statistically significant upregulation (logFC > 0.5, P < 0.0005), consistent with their role in cholesterol biosynthesis and lipid metabolism. b Top KEGG pathways under the control of YAP1 in HCT116 cells. c Graphs assess the expression of SREBF1 and 2 mRNAs by qPCR in cells treated with scrambled or YAP1 siRNAs. Gene expressions were normalized to ACTIN and TUBULIN mRNAs used as internal controls. Data were obtained from 3 independent experiments performed in triplicates and represent ±SEM *P < 0.05, * *P < 0.01, *** P < 0.001 ( t -test). d ChIP-seq data from ENCODE indicating the binding of TEAD4 to transcriptional regulatory regions of SREBF genes. e ChIP assays of YAP1 for binding in complex with TEAD4 to SREBF genes in HCT116 cells, both in the presence and absence of STAT1 and/or YAP1. IgG, non-specific control antibody. f Immunoblotting of SREBP1 and 2 in isogenic pair colon cancer cells prior to and after YAP1 downregulation by siRNAs. FL, full length. g Immunoblotting of SREBP1, 2 and TEAD4 in isogenic pairs of colon cancer cells treated with scrambled or TEAD4 siRNAs. h Immunoblotting of SREBP1 and 2 proteins in HCT116 cells treated with TEAD inhibitor 15 μM VT104 for the indicated time points. f , g , h Quantification of proteins normalized to TUBULIN for each blot is indicated.

Article Snippet: Fluvastatin, cerivastatin, afatinib and BI-2865 were purchased from MedChemExpress, VT104 was acquired from DC Chemicals, Y-27632 was sourced from Selleckhem and 4’,6-diamidino-2-phenylindole (DAPI) was obtained from Roche.

Techniques: Control, Labeling, Expressing, ChIP-sequencing, Binding Assay, Western Blot

Journal: Communications Biology

Article Title: A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer

doi: 10.1038/s42003-025-08740-2

Figure Lengend Snippet: a , b HCT116 cells with intact or depleted STAT1 and/or YAP1 expression were subcutaneously transplanted into female nu/nu mice (n = 10 per group). Tumor volume (mm³) was measured over the indicated time course. At the end of the study, tumor tissues from 3 mice were analyzed by IHC to assess H&E staining and the subcellular localization of YAP1 ( b ). c , d Similarly, HCT116 cells with combined YAP1 and STAT1 deletion or expression were transplanted into nu/nu mice (n = 5 per group). When tumors reached ~200 mm 3 , mice were treated by oral gavage with either vehicle or cerivastatin (CERI). Tumor growth was monitored over time. Red and blue arrows indicate the start point of treatment of YAP1 +/+ STAT1 +/+ and YAP1 −/− STAT1 −/− tumors, respectively. At the endpoint, tumors from 3 mice were subjected to IHC for H&E and YAP1 detection ( d ). a–d Data represent mean ± SEM. Statistical significance was determined by t -test: * P < 0.05, ** P < 0.01, *** P < 0.001. Scale bar in panels b and d: 50 μm and 25 μm (insert image). Quantification graphs panels b and d show Histo (H)-scores for nuclear and cytoplasmic YAP1 staining. e HCT116 xenografts were established in nu/nu mice (n = 5 per group). Upon tumor growth to ~200 mm 3 (red arrow), mice received either vehicle, cerivastatin (oral), afatinib (intraperitoneal), or the combination of both. Tumor volume was tracked for the indicated duration. Data represent mean ± SEM. *** P < 0.001 (t-test). f In a similar setup, mice bearing HCT116 xenografts (~200 mm 3 tumors) were treated with vehicle, cerivastatin (oral), VT104 (oral), or their combination. Tumor growth was monitored throughout the experiment. Data represent mean ± SEM. ** P < 0.01 (t-test). g This schematic model illustrates how the STAT1–YAP1 signaling axis enhances the mevalonate pathway, thereby supporting tumor growth and chemoresistance in mutant KRAS CRC. Inhibiting YAP1-TEAD4 activity (e.g., using VT104) disrupts the SREBP-driven feedback loop that sustains mevalonate pathway activation. Additionally, pharmacological blockade of the mevalonate pathway with statins increases tumor sensitivity to YAP1–TEAD4 inhibition in xenograft models of mutant KRAS CRC.

Article Snippet: Fluvastatin, cerivastatin, afatinib and BI-2865 were purchased from MedChemExpress, VT104 was acquired from DC Chemicals, Y-27632 was sourced from Selleckhem and 4’,6-diamidino-2-phenylindole (DAPI) was obtained from Roche.

Techniques: Expressing, Staining, Mutagenesis, Activity Assay, Activation Assay, Inhibition