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The Hiebert Laboratory

Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma

AUTHORS

Short SPSarah P , Barrett CWCaitlyn W , Stengel KRKristy R , Revetta FLFrank L , Choksi YAYash A , Coburn LALori A , Lintel MKMary K , McDonough EMElizabeth M , Washington MKM Kay , Wilson KTKeith T , Prokhortchouk EEgor , Chen XXi , Hiebert SWScott W , Reynolds ABAlbert B , Williams CSChristopher S . Oncogene. 2019 03 11; 38(25). 5091-5106

ABSTRACT

The myeloid translocation gene family member MTG16 is a transcriptional corepressor that relies on the DNA-binding ability of other proteins to determine specificity. One such protein is the ZBTB family member Kaiso, and the MTG16:Kaiso interaction is necessary for repression of Kaiso target genes, such as matrix metalloproteinase-7. Using the azoxymethane and dextran sodium sulfate (AOM/DSS) murine model of colitis-associated carcinoma, we previously determined that MTG16 loss accelerates tumorigenesis and inflammation. However, it was unknown whether this effect was modified by Kaiso-dependent transcriptional repression. To test for a genetic interaction between MTG16 and Kaiso in inflammatory carcinogenesis, we subjected single and double knockout (DKO) mice to the AOM/DSS protocol. Mtg16 mice demonstrated increased colitis and tumor burden; in contrast, disease severity in Kaiso mice was equivalent to wild-type controls. Surprisingly, Kaiso deficiency in the context of MTG16 loss reversed injury and pro-tumorigenic responses in the intestinal epithelium following AOM/DSS treatment, and tumor numbers were returned to near to wild-type levels. Transcriptomic analysis of non-tumor colon tissue demonstrated that changes induced by MTG16 loss were widely mitigated by concurrent Kaiso loss, and DKO mice demonstrated downregulation of metabolism and cytokine-associated gene sets with concurrent activation of DNA damage checkpoint pathways as compared with Mtg16. Further, Kaiso knockdown in intestinal enteroids reduced stem- and WNT-associated phenotypes, thus abrogating the induction of these pathways observed in Mtg16 samples. Together, these data suggest that Kaiso modifies MTG16-driven inflammation and tumorigenesis and suggests that Kaiso deregulation contributes to MTG16-dependent colitis and CAC phenotypes.