Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
| Autor: | Sarah P. Short, Kristy R. Stengel, Keith T. Wilson, Caitlyn W. Barrett, Albert B. Reynolds, Lori A. Coburn, Yash A. Choksi, Elizabeth M. McDonough, Scott W. Hiebert, M. Kay Washington, Frank Revetta, Egor Prokhortchouk, Christopher S. Williams, Xi Chen, Mary K. Lintel |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Carcinogenesis Context (language use) Adenocarcinoma Biology medicine.disease_cause Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Genetics medicine Animals Humans Kaiso Intestinal Mucosa Colitis Molecular Biology Inflammation Mice Knockout Gene knockdown Azoxymethane colitis-associated carcinoma myeloid translocation gene G2-M DNA damage checkpoint HCT116 Cells medicine.disease Intestinal epithelium MTG16 3. Good health Mice Inbred C57BL Repressor Proteins HEK293 Cells 030104 developmental biology chemistry 030220 oncology & carcinogenesis Colonic Neoplasms Cancer research Female Transcription Factors |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-019-0777-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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