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Myeloid translocation genes differentially regulate colorectal cancer programs

Oncogene volume 35, pages 6341–6349 (2016)Cite this article

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Abstract

Myeloid translocation genes (MTGs), originally identified as chromosomal translocations in acute myelogenous leukemia, are transcriptional corepressors that regulate hematopoietic stem cell programs. Analysis of The Cancer Genome Atlas (TCGA) database revealed that MTGs were mutated in epithelial malignancy and suggested that loss of function might promote tumorigenesis. Genetic deletion of MTGR1 and MTG16 in the mouse has revealed unexpected and unique roles within the intestinal epithelium. Mtgr1−/− mice have progressive depletion of all intestinal secretory cells, and Mtg16−/− mice have a decrease in goblet cells. Furthermore, both Mtgr1−/− and Mtg16−/− mice have increased intestinal epithelial cell proliferation. We thus hypothesized that loss of MTGR1 or MTG16 would modify Apc1638/+-dependent intestinal tumorigenesis. Mtgr1−/− mice, but not Mtg16−/− mice, had a 10-fold increase in tumor multiplicity. This was associated with more advanced dysplasia, including progression to invasive adenocarcinoma, and augmented intratumoral proliferation. Analysis of chromatin immunoprecipitation sequencing data sets for MTGR1 and MTG16 targets indicated that MTGR1 can regulate Wnt and Notch signaling. In support of this, immunohistochemistry and gene expression analysis revealed that both Wnt and Notch signaling pathways were hyperactive in Mtgr1−/− tumors. Furthermore, in human colorectal cancer (CRC) samples MTGR1 was downregulated at both the transcript and protein level. Overall our data indicates that MTGR1 has a context-dependent effect on intestinal tumorigenesis.

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Acknowledgements

We thank the members of the Williams lab, and Karie Ballard for help in revising and proofreading the manuscript. We also thank Dr R Daniel Beauchamp, David Bader and Barbara Fingleton for their advice and counsel in preparing the manuscript. This work was supported by the National Institutes of Health Grants K08DK080221, R01DK099204 (to CSW), P50CA095103 (to MKW), 1F30DK096718 (to BP), 1F31 CA167920 (to CWB), T32 GM07347 (NIH/NIGMS) (to BP), Merit Review Grant from the Office of Medical Research, Department of Veterans Affairs 1I01BX001426 (to CSW), ACS-RSG 116552 (to CSW), R01AT004821 (to KTW), P30DK058404 (Vanderbilt Digestive Disease Research Center), NIH Grant UL1TR000445 (Vanderbilt CTSA). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA

    B Parang, A M Bradley, M K Mittal, S P Short, J J Thompson, C W Barrett, R D Naik, A J Bilotta, K T Wilson & C S Williams

  2. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    B Parang, A M Bradley, M K Mittal, S P Short, J J Thompson, C W Barrett, K T Wilson & C S Williams

  3. Department of Pathology, Microbiology, and Immunology, Nashville, TN, USA

    M K Washington & F L Revetta

  4. Department of Surgery, Division of Surgical Oncology, Nashville, TN, USA

    J J Smith

  5. Department of Biostatistics, Nashville, TN, USA

    X Chen

  6. Vanderbilt Ingram Cancer Center, Nashville, TN, USA

    K T Wilson, S W Hiebert & C S Williams

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

    K T Wilson & C S Williams

  8. Department of Biochemistry, Nashville, TN, USA

    S W Hiebert

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Parang, B., Bradley, A., Mittal, M. et al. Myeloid translocation genes differentially regulate colorectal cancer programs. Oncogene 35, 6341–6349 (2016). https://doi.org/10.1038/onc.2016.167

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