UC San Diego

The long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) maintains the integrity of the intestinal epithelial barrier and regulates local inflammation. However, its influences on intestinal microbial communities and tissue susceptibility to cancer development remain unexplored. Here, we report that MALAT1 regulates host anti-microbial response gene expression and the composition of mucosal-associated microbial communities in a region-specific manner. In the APC mutant mouse model of intestine tumorigenesis, knocking out MALAT1 results in higher polyp counts in the small intestine and colon. Interestingly, intestine polyps that developed in the absence of MALAT1 were smaller in size. These findings highlight the unexpected bivalent role of MALAT1 in restricting and promoting cancer progression at different disease stages. Among the 30 MALAT1-targets shared by both the small intestine and colon, ZNF638 and SENP8 levels are predictive of colon adenoma patient overall survival and disease-free survival. Genomic assays further revealed that MALAT1 modulates intestinal target expression and splicing through both direct and indirect mechanisms. This study expands the role of lncRNAs in regulating intestine homeostasis, microbial communities, and cancer pathogenesis.