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.
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Change history
08 May 2019
In the original version of this article the authors noted that the GEO accession number for the relevant dataset was listed incorrectly as GSE12454.
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Acknowledgements
The authors thank members of the Williams and Reynolds laboratories for thoughtful discussions about this research project. We would also like to thank the Vanderbilt Translational Pathology Shared Resource for aid with histology and the Vanderbilt Technologies for Advanced Genomics for next gen sequencing.
Funding
National Institutes of Health (R01DK099204 to CSW; R01AT004821 to KTW; R01CA178030 to SWH; 1F31CA167920 to CWB; F32DK108492 to SPS); the Federal Research Center “Fundamentals of Biotechnology” budget (No. 01201371085 to EP); Office of Medical Research, Department of Veterans Affairs (1I01BX001426 to CSW; 1I01BX001453 to KTW; 1IK2BX002126 to LAC). Additional support was provided by the NIH grant P30DK058404 (Vanderbilt Digestive Disease Research Center).
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SPS, CWB, KRS, KTW, EP, SWH, ABR and CSW: study conception and/or design; SPS, CWB, KRS, FLR, YAC, LAC, MKL and EMM: data acquisition; SPS, CWB, KRS, YAC, MKW, XC and CSW: data analysis; SPS, CWB, LAC, MKW, KTW, EP and SWH: financial support. All authors contributed to paper generation and approval.
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Short, S.P., Barrett, C.W., Stengel, K.R. et al. Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma. Oncogene 38, 5091–5106 (2019). https://doi.org/10.1038/s41388-019-0777-7
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DOI: https://doi.org/10.1038/s41388-019-0777-7