Journal article
Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
Oncogene, Vol.38(25), pp.5091-5106
06/20/2019
DOI: 10.1038/s41388-019-0777-7
PMCID: PMC6586520
PMID: 30858547
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.
Details
- Title: Subtitle
- Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma
- Creators
- Sarah P Short - Vanderbilt UniversityCaitlyn W Barrett - Vanderbilt UniversityKristy R Stengel - Vanderbilt UniversityFrank L Revetta - Vanderbilt University Medical CenterYash A Choksi - Vanderbilt UniversityLori A Coburn - Vanderbilt UniversityMary K Lintel - Vanderbilt University Medical CenterElizabeth M McDonough - Our Lady of the Lake Children's HospitalM Kay Washington - Vanderbilt University Medical CenterKeith T Wilson - Vanderbilt UniversityEgor Prokhortchouk - BioengineeringXi Chen - University of MiamiScott W Hiebert - Vanderbilt UniversityAlbert B Reynolds - Vanderbilt Ingram Cancer Center, Nashville, TN, 37232, USAChristopher S Williams - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.38(25), pp.5091-5106
- DOI
- 10.1038/s41388-019-0777-7
- PMID
- 30858547
- PMCID
- PMC6586520
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Grant note
- R01 AT004821 / NCCIH NIH HHS P50 CA236733 / NCI NIH HHS R01 CA164605 / NCI NIH HHS IK2 BX002126 / BLRD VA R01 DK099204 / NIDDK NIH HHS P30 DK058404 / NIDDK NIH HHS I01 BX001453 / BLRD VA R01 CA178030 / NCI NIH HHS F32 DK108492 / NIDDK NIH HHS F31 CA167920 / NCI NIH HHS I01 BX001426 / BLRD VA
- Language
- English
- Date published
- 06/20/2019
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420846602771
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