Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma

Oncogene volume 38, pages 5091–5106 (2019)Cite this article

Subjects

A Correction to this article was published on 08 May 2019

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

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.

References

  1. Daniel JM, Reynolds AB. The cateninp120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol Cell Biol. 1999;19:3614–23.

    Article  CAS  Google Scholar 

  2. Spring CM, Kelly KF, O’Kelly I, Graham M, Crawford HC, Daniel JM. The catenin p120ctn inhibits Kaiso-mediated transcriptional repression of the beta-catenin/TCF target gene matrilysin. Exp Cell Res. 2005;305:253–65.

    Article  CAS  Google Scholar 

  3. Lopes EC, Valls E, Figueroa ME, Mazur A, Meng FG, Chiosis G, et al. Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines. Cancer Res. 2008;68:7258–63.

    Article  CAS  Google Scholar 

  4. Filion GJ, Zhenilo S, Salozhin S, Yamada D, Prokhortchouk E, Defossez PA. A family of human zinc finger proteins that bind methylated DNA and repress transcription. Mol Cell Biol. 2006;26:169–81.

    Article  CAS  Google Scholar 

  5. Buck-Koehntop BA, Martinez-Yamout MA, Dyson HJ, Wright PE. Kaiso uses all three zinc fingers and adjacent sequence motifs for high affinity binding to sequence-specific and methyl-CpG DNA targets. FEBS Lett. 2012;586:734–9.

    Article  CAS  Google Scholar 

  6. Donaldson IJ, Amin S, Hensman JJ, Kutejova E, Rattray M, Lawrence N, et al. Genome-wide occupancy links Hoxa2 to Wnt-beta-catenin signaling in mouse embryonic development. Nucleic Acids Res. 2012;40:3990–4001.

    Article  CAS  Google Scholar 

  7. Park JI, Kim SW, Lyons JP, Ji H, Nguyen TT, Cho K, et al. Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets. Dev Cell. 2005;8:843–54.

    Article  CAS  Google Scholar 

  8. Pozner A, Terooatea TW, Buck-Koehntop BA. Cell-specific Kaiso (ZBTB33) regulation of cell cycle through cyclin D1 and cyclin E1. J Biol Chem. 2016;291:24538–50.

    Article  CAS  Google Scholar 

  9. Ruzov A, Savitskaya E, Hackett JA, Reddington JP, Prokhortchouk A, Madej MJ, et al. The non-methylated DNA-binding function of Kaiso is not required in early Xenopus laevis development. Development. 2009;136:729–38.

    Article  CAS  Google Scholar 

  10. Davis JN, McGhee L, Meyers S. The ETO (MTG8) gene family. Gene. 2003;303:1–10.

    Article  CAS  Google Scholar 

  11. Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie JR, et al. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol. 1998;18:7176–84.

    Article  CAS  Google Scholar 

  12. Barrett CW, Smith JJ, Lu LC, Markham N, Stengel KR, Short SP, et al. Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters. PLoS ONE. 2012;7:e51205.

    Article  CAS  Google Scholar 

  13. Kochetkova M, McKenzie OL, Bais AJ, Martin JM, Secker GA, Seshadri R, et al. CBFA2T3 (MTG16) is a putative breast tumor suppressor gene from the breast cancer loss of heterozygosity region at 16q24.3. Cancer Res. 2002;62:4599–604.

    CAS  PubMed  Google Scholar 

  14. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–74.

    Article  Google Scholar 

  15. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–13.

    Article  CAS  Google Scholar 

  16. Barrett CW, Fingleton B, Williams A, Ning W, Fischer MA, Washington MK, et al. MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model. Cancer Res. 2011;71:1302–12.

    Article  CAS  Google Scholar 

  17. Pierre CC, Longo J, Mavor M, Milosavljevic SB, Chaudhary R, Gilbreath E, et al. Kaiso overexpression promotes intestinal inflammation and potentiates intestinal tumorigenesis in Apc(Min/+) mice. Biochim Biophys Acta. 2015;1852:1846–55.

    Article  CAS  Google Scholar 

  18. Chaudhary R, Pierre CC, Nanan K, Wojtal D, Morone S, Pinelli C, et al. The POZ-ZF transcription factor Kaiso (ZBTB33) induces inflammation and progenitor cell differentiation in the murine intestine. PLoS ONE. 2013;8:e74160.

    Article  CAS  Google Scholar 

  19. Prokhortchouk A, Sansom O, Selfridge J, Caballero IM, Salozhin S, Aithozhina D, et al. Kaiso-deficient mice show resistance to intestinal cancer. Mol Cell Biol. 2006;26:199–208.

    Article  CAS  Google Scholar 

  20. The Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

  21. McDonough EM, Barrett CW, Parang B, Mittal MK, Smith JJ, Bradley AM, et al. MTG16 is a tumor suppressor in colitis-associated carcinoma. JCI Insight. 2017;2.

  22. Becker C, Fantini MC, Wirtz S, Nikolaev A, Kiesslich R, Lehr HA, et al. In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy. Gut. 2005;54:950–4.

    Article  CAS  Google Scholar 

  23. Williams CS, Bradley AM, Chaturvedi R, Singh K, Piazuelo MB, Chen X. MTG16 contributes to colonic epithelial integrity in experimental colitis. Gut. 2012;62:1446–55.

    Article  Google Scholar 

  24. Poindexter SV, Reddy VK, Mittal MK, Williams AM, Washington MK, Harris E, et al. Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury. Am J Physiol Gastrointest Liver Physiol. 2015;308:G562–71.

    Article  CAS  Google Scholar 

  25. Nowarski R, Jackson R, Gagliani N, de Zoete MR, Palm NW, Bailis W, et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell. 2015;163:1444–56.

    Article  CAS  Google Scholar 

  26. Bergstrom KS, Guttman JA, Rumi M, Ma C, Bouzari S, Khan MA, et al. Modulation of intestinal goblet cell function during infection by an attaching and effacing bacterial pathogen. Infect Immun. 2008;76:796–811.

    Article  CAS  Google Scholar 

  27. McCormick DA, Horton LW, Mee AS. Mucin depletion in inflammatory bowel disease. J Clin Pathol. 1990;43:143–6.

    Article  CAS  Google Scholar 

  28. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  Google Scholar 

  29. Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27:1739–40.

    Article  CAS  Google Scholar 

  30. Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science. 1989;246:629–34.

    Article  CAS  Google Scholar 

  31. Syljuasen RG, Krolewski B, Little JB. Loss of normal G1 checkpoint control is an early step in carcinogenesis, independent of p53 status. Cancer Res. 1999;59:1008–14.

    CAS  PubMed  Google Scholar 

  32. Rudolph KL, Hartmann D, Opitz OG. Telomere dysfunction and DNA damage checkpoints in diseases and cancer of the gastrointestinal tract. Gastroenterology. 2009;137:754–62.

    Article  CAS  Google Scholar 

  33. Raghav SK, Waszak SM, Krier I, Gubelmann C, Isakova A, Mikkelsen TS, et al. Integrative genomics identifies the corepressor SMRT as a gatekeeper of adipogenesis through the transcription factors C/EBPbeta and KAISO. Mol Cell. 2012;46:335–50.

    Article  CAS  Google Scholar 

  34. Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, et al. Systematic discovery of regulatory motifs in human promoters and 3’ UTRs by comparison of several mammals. Nature. 2005;434:338–45.

    Article  CAS  Google Scholar 

  35. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262–5.

    Article  CAS  Google Scholar 

  36. Reddy VK, Short SP, Barrett CW, Mittal MK, Keating CE, Thompson JJ, et al. BVES regulates intestinal stem cell programs and intestinal crypt viability after radiation. Stem Cells. 2016;34:1626–36.

    Article  CAS  Google Scholar 

  37. Miyoshi H, Stappenbeck TS. In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat Protoc. 2013;8:2471–82.

    Article  CAS  Google Scholar 

  38. Kim SW, Park JI, Spring CM, Sater AK, Ji H, Otchere AA, et al. Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin. Nat Cell Biol. 2004;6:1212–20.

    Article  CAS  Google Scholar 

  39. Li Q, Ishikawa TO, Oshima M, Taketo MM. The threshold level of adenomatous polyposis coli protein for mouse intestinal tumorigenesis. Cancer Res. 2005;65:8622–7.

    Article  CAS  Google Scholar 

  40. Buchert M, Athineos D, Abud HE, Burke ZD, Faux MC, Samuel MS, et al. Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo. PLoS Genet. 2010;6:e1000816.

    Article  Google Scholar 

  41. Christie M, Jorissen RN, Mouradov D, Sakthianandeswaren A, Li S, Day F, et al. Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/beta-catenin signalling thresholds for tumourigenesis. Oncogene. 2013;32:4675–82.

    Article  CAS  Google Scholar 

  42. Koch S, Nava P, Addis C, Kim W, Denning TL, Li L, et al. The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair. Gastroenterology. 2011;141:259–68, 68 e1–8.

    Article  CAS  Google Scholar 

  43. Martinez JA, Williams CS, Amann JM, Ellis TC, Moreno-Miralles I, Washington MK, et al. Deletion of Mtgr1 sensitizes the colonic epithelium to dextran sodium sulfate-induced colitis. Gastroenterology. 2006;131:579–88.

    Article  CAS  Google Scholar 

  44. Blattler A, Yao L, Wang Y, Ye Z, Jin VX, Farnham PJ. ZBTB33 binds unmethylated regions of the genome associated with actively expressed genes. Epigenetics Chromatin. 2013;6:13.

    Article  CAS  Google Scholar 

  45. Becker C, Fantini MC, Neurath MF. High resolution colonoscopy in live mice. Nat Protoc. 2006;1:2900–4.

    Article  CAS  Google Scholar 

  46. Brown JJ, Short SP, Stencel-Baerenwald J, Urbanek K, Pruijssers AJ, McAllister N, et al. Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection. J Virol. 2018;92.

  47. Heijmans J, van Lidth de Jeude JF, Koo BK, Rosekrans SL, Wielenga MC, van de Wetering M, et al. ER stress causes rapid loss of intestinal epithelial stemness through activation of the unfolded protein response. Cell Rep. 2013;3:1128–39.

    Article  CAS  Google Scholar 

  48. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–20.

    Article  CAS  Google Scholar 

  49. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 2012;7:562–78.

    Article  CAS  Google Scholar 

  50. Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207–10.

    Article  CAS  Google Scholar 

  51. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.

    Article  CAS  Google Scholar 

Download references

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).

Author information

Author notes

  1. These authors contributed equally: Sarah P. Short, Caitlyn W. Barrett

Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Sarah P. Short, Caitlyn W. Barrett, Yash A. Choksi, Lori A. Coburn, Mary K. Lintel, Elizabeth M. McDonough, Keith T. Wilson & Christopher S. Williams

  2. Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA

    Sarah P. Short, Caitlyn W. Barrett, Yash A. Choksi, Keith T. Wilson, Albert B. Reynolds & Christopher S. Williams

  3. Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA

    Kristy R. Stengel & Scott W. Hiebert

  4. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Frank L. Revetta, M. Kay Washington & Keith T. Wilson

  5. Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, 37232, USA

    Yash A. Choksi, Lori A. Coburn, Keith T. Wilson & Christopher S. Williams

  6. Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Lori A. Coburn, Keith T. Wilson & Christopher S. Williams

  7. Department of Pediatrics, Division of Gastroenterology, Our Lady of the Lake Children’s Hospital, Baton Rouge, TN, 70808, USA

    Elizabeth M. McDonough

  8. Vanderbilt Ingram Cancer Center, Nashville, TN, 37232, USA

    Keith T. Wilson, Scott W. Hiebert, Albert B. Reynolds & Christopher S. Williams

  9. Institute of Bioengineering, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow, Russia

    Egor Prokhortchouk

  10. Department of Public Health Sciences and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Xi Chen

Authors
  1. Sarah P. Short
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caitlyn W. Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristy R. Stengel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frank L. Revetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yash A. Choksi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lori A. Coburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mary K. Lintel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elizabeth M. McDonough
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Kay Washington
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Keith T. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Egor Prokhortchouk
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Scott W. Hiebert
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Albert B. Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Christopher S. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Christopher S. Williams.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0777-7

Search

Advanced search

Quick links