Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:38 |
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| Enthalten in: |
Oncogene - 38(2019), 25 vom: 11. Juni, Seite 5091-5106 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Short, Sarah P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.12.2019 Date Revised 20.04.2022 published: Print-Electronic ErratumIn: Oncogene. 2019 May 8;:. - PMID 31068667 Citation Status MEDLINE |
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| doi: |
10.1038/s41388-019-0777-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM294820663 |
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| 100 | 1 | |a Short, Sarah P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 17.12.2019 | ||
| 500 | |a Date Revised 20.04.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: Oncogene. 2019 May 8;:. - PMID 31068667 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 700 | 1 | |a Barrett, Caitlyn W |e verfasserin |4 aut | |
| 700 | 1 | |a Stengel, Kristy R |e verfasserin |4 aut | |
| 700 | 1 | |a Revetta, Frank L |e verfasserin |4 aut | |
| 700 | 1 | |a Choksi, Yash A |e verfasserin |4 aut | |
| 700 | 1 | |a Coburn, Lori A |e verfasserin |4 aut | |
| 700 | 1 | |a Lintel, Mary K |e verfasserin |4 aut | |
| 700 | 1 | |a McDonough, Elizabeth M |e verfasserin |4 aut | |
| 700 | 1 | |a Washington, M Kay |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Keith T |e verfasserin |4 aut | |
| 700 | 1 | |a Prokhortchouk, Egor |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Hiebert, Scott W |e verfasserin |4 aut | |
| 700 | 1 | |a Reynolds, Albert B |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Christopher S |e verfasserin |4 aut | |
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