Myeloid translocation genes differentially regulate colorectal cancer programs

• Published in: Oncogene 2016-12, Vol.35 (49), p.6341-6349
• Main Authors: Parang, B, Bradley, A M, Mittal, M K, Short, S P, Thompson, J J, Barrett, C W, Naik, R D, Bilotta, A J, Washington, M K, Revetta, F L, Smith, J J, Chen, X, Wilson, K T, Hiebert, S W, Williams, C S
• Format: Article
• Language: English
• Subjects: 14/105; 631/67/1504/1885; 631/67/581; 64/60; 82/51; Acute myeloid leukemia; Adenocarcinoma; Animals; Apoptosis; Carcinogenesis; Cell Biology; Cell proliferation; Cellular signal transduction; Chromatin; Chromosome translocations; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Development and progression; Dysplasia; Epithelial cells; Epithelium; Female; Gene expression; Genetic aspects; Genomes; Goblet cells; Hematopoietic stem cells; Human Genetics; Humans; Immunohistochemistry; Immunoprecipitation; Internal Medicine; Intestine; Invasiveness; Leukemia; Male; Malignancy; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology; original-article; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction; Stem cells; Transcription; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Translocation, Genetic; Translocations (Genetics); Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Wnt protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.167

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 Apc 1638/+ -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.