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

Sarah P. Short, Caitlyn W. Barrett, Kristy R. Stengel, Frank L. Revetta, Yash A. Choksi, Lori A. Coburn, Mary K. Lintel, Elizabeth M. McDonough, M. Kay Washington, Keith T. Wilson, Egor Prokhortchouk, Xi Chen, Scott W. Hiebert, Albert B. Reynolds, Christopher S. Williams

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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.

Original languageEnglish (US)
Pages (from-to)5091-5106
Number of pages16
JournalOncogene
Volume38
Issue number25
DOIs
StatePublished - Jun 20 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Short, S. P., Barrett, C. W., Stengel, K. R., Revetta, F. L., Choksi, Y. A., Coburn, L. A., Lintel, M. K., McDonough, E. M., Washington, M. K., Wilson, K. T., Prokhortchouk, E., Chen, X., Hiebert, S. W., Reynolds, A. B., & Williams, C. S. (2019). Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma. Oncogene, 38(25), 5091-5106. https://doi.org/10.1038/s41388-019-0777-7