Deletion of CUL4B in gut epithelium promotes ApcMin/+ adenoma formation by impacting the microenvironment

Abstract

Abstract Cullin 4B (CUL4B) is a scaffold protein of the E3 ubiquitin ligase complex. Recent studies have reported the converse effect of CUL4B in carcinogenesis depending on where it functions. The role of CUL4B in tumor initiation at pre-tumor stage remains unknown. Here we report that CUL4B deficiency in the gut epithelium accelerates ApcMin/+ adenoma formation by creating the adenoma-prone immunosuppressive microenvironment. Absence of epithelial CUL4B improves the recruitment and activation of tumor-infiltrating CD11b+Gr-1+ MDSCs. In vitro co-culture of MDSCs significantly rescued the reverse phenotype of CUL4B deficient organoids. Mechanistically, CUL4B transcriptionally represses the expression of Csf3, one gene encoding secreted chemokine responsible for enrolling MDSCs. Our findings provide an understanding of the interplay between adenoma cells and microenvironment in promoting colorectal cancer (CRC) initiation in the context of activated Wnt.