RIP140 Represses Intestinal Paneth Cell Differentiation and Interplays with SOX9 Signaling in Colorectal Cancer

SIMPLE SUMMARY: In the small intestine, the transcription factor SOX9 regulates the differentiation of Paneth cells, which are key actors in the intestinal antimicrobial defense and stem cell niche. SOX9 is also an important player in colon cancer development and progression. In this study, we demonstrate that the transcription coregulator RIP140 inhibits SOX9 expression and activity. Consequently, RIP140 and SOX9 exert opposite effects on Paneth cell differentiation and colon cancer cell proliferation. Their expression undergoes inverse regulation by the Wnt signaling pathway and inversely correlates with survival of patient with colon cancer. These results identify RIP140 as a major regulator of SOX9 signaling with functional relevance in intestinal physiopathology. ABSTRACT: RIP140 is a major transcriptional coregulator of gut homeostasis and tumorigenesis through the regulation of Wnt/APC signaling. Here, we investigated the effect of RIP140 on Paneth cell differentiation and its interplay with the transcription factor SOX9. Using loss of function mouse models, human colon cancer cells, and tumor microarray data sets we evaluated the role of RIP140 in SOX9 expression and activity using RT-qPCR, immunohistochemistry, luciferase reporter assays, and GST-pull down. We first evidence that RIP140 strongly represses the Paneth cell lineage in the intestinal epithelium cells by inhibiting Sox9 expression. We then demonstrate that RIP140 interacts with SOX9 and inhibits its transcriptional activity. Our results reveal that the Wnt signaling pathway exerts an opposite regulation on SOX9 and RIP140. Finally, the levels of expression of RIP140 and SOX9 exhibit a reverse response and prognosis value in human colorectal cancer biopsies. This work highlights an intimate transcriptional cross-talk between RIP140 and SOX9 in intestinal physiopathology.