ECSIT Is a Critical Factor for Controlling Intestinal Homeostasis and Tumorigenesis through Regulating the Translation of YAP Protein

The intestinal epithelium is the fastest renewing tissue in mammals and its regenerative process must be tightly controlled to minimize the risk of dysfunction and tumorigenesis. The orderly expression and activation of Yes‐associated protein (YAP) are the key steps in driving intestinal regeneration and crucial for intestinal homeostasis. However, the regulatory mechanisms controlling this process remain largely unknown. Here, it is discovered that evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), a multi‐functional protein, is enriched along the crypt–villus axis. Intestinal cell‐specific ablation of ECSIT results in the dysregulation of intestinal differentiation unexpectedly accompanied with enhanced YAP protein dependent on translation, thus transforming intestinal cells to early proliferative stem “‐like” cells and augmenting intestinal tumorigenesis. Loss of ECSIT leads to metabolic reprogramming in favor of amino acid–based metabolism, which results in demethylation of genes encoding the eukaryotic initiation factor 4F pathway and their increased expression that further promotes YAP translation initiation culminating in intestinal homeostasis imbalance and tumorigenesis. It is also shown that the expression of ECSIT is positively correlated with the survival of patients with colorectal cancer. Together, these results demonstrate the important role of ECSIT in regulating YAP protein translation to control intestinal homeostasis and tumorigenesis. The study provides a molecular framework that defines the importance of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) in regulating Yes‐associated protein (YAP) protein translation to control intestinal tumorigenesis: Loss of ECSIT leads to metabolic reprogramming in favor of amino acid‐based metabolism, which results in demethylation of genes encoding the eukaryotic initiation factor 4F pathway and further promotes YAP translation initiation culminating in intestinal homeostasis imbalance and tumorigenesis.