TNF-α-responsive YAP1 promotes CCL20 expression in colorectal inflammation and cancer

Abstract

Colitis-associated colorectal cancer (CAC) exemplifies how chronic intestinal inflammation can be converted into sustained epithelial programs and a permissive tumor microenvironment, yet the molecular linkage between inflammatory cytokine cues and chemokine outputs remains incompletely defined. Here, we identify a TNF-α-responsive YAP1–CCL20 program in colorectal inflammation and cancer. Across public cohorts and clinical specimens, YAP1 was elevated in ulcerative colitis and colorectal cancer and positively correlated with TNF-α expression. TNF-α increased YAP1 mRNA in both NCM460 and HCT116 cells. In HCT116 cells, TNF-α also increased YAP1 protein abundance and promoted its nuclear accumulation, whereas infliximab attenuated TNF-α-induced YAP1 mRNA and protein upregulation. Transcriptomic profiling following YAP1 silencing highlighted CCL20 among the most markedly downregulated genes. YAP1 gain- and loss-of-function consistently regulated CCL20 expression and secretion, and mechanistic assays demonstrated that YAP1/TEAD activity directly transactivated the CCL20 promoter. Functionally, TNF-α enhanced proliferation, migration, and invasion of colorectal cancer cells, effects that were blunted by YAP1 knockdown; CCL20 overexpression partially rescued the suppressed malignant phenotypes caused by YAP1 silencing. In vivo, verteporfin and/or infliximab ameliorated DSS-induced colitis, accompanied by reduced colonic Yap1 and Ccl20 expression, lower serum CCL20, and diminished mucosal accumulation of CD3⁺ T cells, CD19⁺ B cells, CD11c⁺ dendritic cells, and FOXP3⁺ regulatory T cells. Moreover, combined YAP pathway inhibition and CCL20 knockdown produced the most pronounced suppression of xenograft tumor growth. Together, these findings position CCL20 as a mechanistically defined downstream effector of YAP1 and suggest that a TNF-α-responsive YAP1–CCL20 program contributes to inflammatory chemokine remodeling in colitis and to malignant phenotypes of colorectal cancer cells.