Cargando…

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 s...

Descripción completa

Detalles Bibliográficos
Autores principales: Short, Sarah P., Barrett, Caitlyn W., Stengel, Kristy R., Revetta, Frank L., Choksi, Yash A., Coburn, Lori A., Lintel, Mary K., Mcdonough, Elizabeth M., Washington, M. Kay, Wilson, Keith T., Prokhortchouk, Egor, Chen, Xi, Hiebert, Scott W., Reynolds, Albert B., Williams, Christopher S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586520/
https://www.ncbi.nlm.nih.gov/pubmed/30858547
http://dx.doi.org/10.1038/s41388-019-0777-7
_version_ 1783428899325083648
author Short, Sarah P.
Barrett, Caitlyn W.
Stengel, Kristy R.
Revetta, Frank L.
Choksi, Yash A.
Coburn, Lori A.
Lintel, Mary K.
Mcdonough, Elizabeth M.
Washington, M. Kay
Wilson, Keith T.
Prokhortchouk, Egor
Chen, Xi
Hiebert, Scott W.
Reynolds, Albert B.
Williams, Christopher S.
author_facet Short, Sarah P.
Barrett, Caitlyn W.
Stengel, Kristy R.
Revetta, Frank L.
Choksi, Yash A.
Coburn, Lori A.
Lintel, Mary K.
Mcdonough, Elizabeth M.
Washington, M. Kay
Wilson, Keith T.
Prokhortchouk, Egor
Chen, Xi
Hiebert, Scott W.
Reynolds, Albert B.
Williams, Christopher S.
author_sort Short, Sarah P.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6586520
institution National Center for Biotechnology Information
language English
publishDate 2019
record_format MEDLINE/PubMed
spelling pubmed-65865202019-09-11 Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma Short, Sarah P. Barrett, Caitlyn W. Stengel, Kristy R. Revetta, Frank L. Choksi, Yash A. Coburn, Lori A. Lintel, Mary K. Mcdonough, Elizabeth M. Washington, M. Kay Wilson, Keith T. Prokhortchouk, Egor Chen, Xi Hiebert, Scott W. Reynolds, Albert B. Williams, Christopher S. Oncogene Article 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. 2019-03-11 2019-06 /pmc/articles/PMC6586520/ /pubmed/30858547 http://dx.doi.org/10.1038/s41388-019-0777-7 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Short, Sarah P.
Barrett, Caitlyn W.
Stengel, Kristy R.
Revetta, Frank L.
Choksi, Yash A.
Coburn, Lori A.
Lintel, Mary K.
Mcdonough, Elizabeth M.
Washington, M. Kay
Wilson, Keith T.
Prokhortchouk, Egor
Chen, Xi
Hiebert, Scott W.
Reynolds, Albert B.
Williams, Christopher S.
Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
title Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
title_full Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
title_fullStr Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
title_full_unstemmed Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
title_short Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
title_sort kaiso is required for mtg16-dependent effects on colitis-associated carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586520/
https://www.ncbi.nlm.nih.gov/pubmed/30858547
http://dx.doi.org/10.1038/s41388-019-0777-7
work_keys_str_mv AT shortsarahp kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT barrettcaitlynw kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT stengelkristyr kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT revettafrankl kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT choksiyasha kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT coburnloria kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT lintelmaryk kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT mcdonoughelizabethm kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT washingtonmkay kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT wilsonkeitht kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT prokhortchoukegor kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT chenxi kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT hiebertscottw kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT reynoldsalbertb kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma
AT williamschristophers kaisoisrequiredformtg16dependenteffectsoncolitisassociatedcarcinoma