Fig. 8

Screening of driver genes and candidate targets or compounds. A Experimental outline of screening and analysis. B Volcano plots to compare differences in sgRNA abundance between fluorouracil- and vehicle-treated cells. C Heatmap showing the counts of sgRNAs representing genes mediating fluorouracil resistance in patients in the HMC4 cluster. D Boxplot of ZEB2 expression in the four studied histone modifier expression patterns in the meta-GEO (left) and TCGA-COAD (right) cohorts. E Scatter plots show the correlation between ZEB2 expression and HM_score value in the SYSUCC cohort. F Boxplot of ZEB2 expression among patients with different fluorouracil responses in the meta-GEO, TCGA-COAD, and SYSUCC cohorts. G Forest plots of the association between ZEB2 expression and overall survival in subgroups stratified by adjuvant chemotherapy conduction (upper) and the benefit of adjuvant chemotherapy in the low- and high-ZEB2 expression groups in the meta-GEO and TCGA-COAD cohorts (down). H Heatmaps of the correlation between ZEB2 expression, tumor microenvironment cell infiltration (left), and pathway activation (right) in the meta-GEO, TCGA-COAD, and SYSUCC cohorts. I Boxplot of ZEB2 expression in different CMS molecular subgroups in the meta-GEO, TCGA-COAD, and SYSUCC cohorts. J Volcano plots to compare differences in the gene expression of histone modification regulators between the low- and high-ZEB2 expression groups in the integrated meta-GEO and TCGA-COAD cohort. K Dose–response curves of SW480 (left) and HCT116 cells (right) transfected with empty vectors or ZEB2 siRNA after fluorouracil treatment for 24 h. The mean ± standard deviation of the three replicates of each time point is shown. L Heatmaps showing the enrichment score of each molecular target (upper) and compound (down) in the Connectivity Map analysis. M Heatmap showing the mechanisms of the action (rows) of each compound in the Connectivity Map analysis. *p < 0.05, **p < 0.01, ***p < 0.001; RFS, relapse-free survival; OS, overall survival; CI, confidence interval; CMS, consensus molecular subtypes; R, response; NR, nonresponse; ADJC, adjuvant chemotherapy; and FC, fold change