RNA-binding Mex3a promotes epithelial stemness and represses Klf4-dependent differentiation upon intestinal homeostasis, regeneration and cancer

The precise control of the self-renewal and differentiation of intestinal stem cells (ISCs) is essential for intestinal homeostasis, efficient regeneration and prevention of tumorigenesis. However, the underlying molecular mechanisms remain only partially understood, especially in regeneration and cancer. Here, it is demonstrated that RNA-binding protein Mex3a is specifically expressed in ISCs and promotes their stemness and proliferative status. Its depletion results in compromised ISCs, impaired intestinal regeneration and suppressed oncogenic transformation. Mechanistically, upregulation of Mex3a in ISCs at homeostasis, in postirradiation regenerative foci and in colorectal cancer model is regulated by the upstream transcription factor E2f3. In turn, Mex3a activates Wnt signaling by directly suppressing pro-differentiation transcription factor Klf4 at the mRNA level. Furthermore, expression of E2F3 and MEX3A significantly increases in human radiation enteritis and colorectal carcinoma (CRC), accompanied by KLF4 downregulation and Wnt signaling hyperactivation. These findings indicate that the E2f3-Mex3a-Klf4-Wnt as the critical molecular switch between ISC self-renewal and differentiation. It can represent a putative therapeutic target for CRC and regeneration-related gut diseases. Intestinal crypt mRNA profiles of 8-week-old wild type (WT) and Mex3a-/- mice