ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer

Abstract Inhibitors of DNA binding and cell differentiation (ID) proteins regulate cellular differentiation and tumor progression. Whether ID family proteins serve as a linkage between pathological differentiation and cancer stemness in colorectal cancer is largely unknown. Here, the expression of ID4, but not other ID family proteins, was enriched in LGR5-high colon cancer stem cells. Its high expression was associated with poor pathological differentiation of colorectal tumors and shorter survival in patients. Knockdown of ID4 inhibited the growth and dissemination of colon cancer cells, while enhancing chemosensitivity. Through gene expression profiling analysis, brain-derived neurotrophic factor (BDNF) was identified as a downstream target of ID4 expression in colorectal cancer. BDNF knockdown decreased the growth and migration of colon cancer cells, and its expression enhanced dissemination, anoikis resistance and chemoresistance. ID4 silencing attenuated the epithelial-to-mesenchymal transition pattern in colon cancer cells. Gene cluster analysis revealed that ID4 and BDNF expression was clustered with mesenchymal markers and distant from epithelial genes. BDNF silencing decreased the expression of mesenchymal markers Vimentin, CDH2 and SNAI1. These findings demonstrated that ID4–BDNF signaling regulates colorectal cancer survival, with the potential to serve as a prognostic marker in colorectal cancer.