Colorectal cancer (CRC) severely threatens human health and life span. An effective therapeutic strategy has not been established because we do not clearly know its pathogenesis. Here, we report that
ceramide and
sterol O-acyltransferase 1 (SOAT1) have roles in both spontaneous and chemical-induced
intestinal cancers. We first found that miRNA-148a deficiency dramatically increased mouse gut
dysbiosis through upregulating
ceramide synthase 5 (Cers5) expression, which promoted
ceramide synthesis afterward. The newly generated
ceramide further promoted both
azoxymethane/
dextran sodium sulfate-induced (AOM/DSS-induced) and ApcMin/+ spontaneous intestinal
tumorigenesis via increasing mouse gut
dysbiosis. Meanwhile, increased level of
ceramide correlated with the significant enhancements of both β-
catenin activity and colorectal
tumorigenesis in a TLR4-dependent fashion. Next, we found a direct binding of β-
catenin to SOAT1 promoter to activate transcriptional expression of SOAT1, which further induced
cholesterol esterification and colorectal
tumorigenesis. In human patients with CRC, the same CERS5/TLR4/β-
catenin/SOAT1 axis was also found to be dysregulated. Finally, the SOAT1 inhibitor (
avasimibe) showed significant levels of
therapeutic effects on both AOM/DSS-induced and ApcMin/+ spontaneous
intestinal cancer. Our study clarified that
ceramide promoted CRC development through increasing gut
dysbiosis, further resulting in the increase of
cholesterol esterification in a SOAT1-dependent way. Treatment with
avasimibe to specifically decrease
cholesterol esterification could be considered as a clinical strategy for effective CRC
therapy in a future study.