USP22 Suppresses SPARC Expression in Acute Colitis and Inflammation-Associated Colorectal Cancer

SIMPLE SUMMARY: Intestinal inflammation leads to an increased risk of developing colorectal cancer (CRC) and incidences are expected to rise. Therefore, it is crucial to identify molecular factors contributing to these medical conditions. In an earlier study, we identified USP22 as a tumor suppressor in CRC since the loss of Usp22 resulted in severe tumor burden in mice. Moreover, Usp22-deficient mice displayed inflammation-associated symptoms. Therefore, we aimed to elucidate the function of USP22 in intestinal inflammation and inflammation-associated CRC. Indeed, mice with an intestine-specific loss of Usp22 displayed more severe colitis compared to wild type controls. In addition, the loss of Usp22 in a mouse model for CRC resulted in increased numbers of inflammation-associated tumors. Finally, we observed that the loss of USP22 induces the expression of Sparc, a factor previously linked to inflammation. Together, our results suggest that USP22 suppresses Sparc expression in acute colitis and inflammation-associated CRC. ABSTRACT: As a member of the 11-gene “death-from-cancer” gene expression signature, ubiquitin-specific protease 22 (USP22) has been considered an oncogene in various human malignancies, including colorectal cancer (CRC). We recently identified an unexpected tumor-suppressive function of USP22 in CRC and detected intestinal inflammation after Usp22 deletion in mice. We aimed to investigate the function of USP22 in intestinal inflammation as well as inflammation-associated CRC. We evaluated the effects of a conditional, intestine-specific knockout of Usp22 during dextran sodium sulfate (DSS)-induced colitis and in a model for inflammation-associated CRC. Mice were analyzed phenotypically and histologically. Differentially regulated genes were identified in USP22-deficient human CRC cells and the occupancy of active histone markers was determined using chromatin immunoprecipitation. The knockout of Usp22 increased inflammation-associated symptoms after DSS treatment locally and systemically. In addition, Usp22 deletion resulted in increased inflammation-associated colorectal tumor growth. Mechanistically, USP22 depletion in human CRC cells induced a profound upregulation of secreted protein acidic and rich in cysteine (SPARC) by affecting H3K27ac and H2Bub1 occupancy on the SPARC gene. The induction of SPARC was confirmed in vivo in our intestinal Usp22-deficient mice. Together, our findings uncover that USP22 controls SPARC expression and inflammation intensity in colitis and CRC.