Myeloid translocation genes differentially regulate colorectal cancer programs.
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.
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
B
B
Parang
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
A M
AM
Bradley
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
M K
MK
Mittal
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
S P
SP
Short
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
J J
JJ
Thompson
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
C W
CW
Barrett
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.
R D
RD
Naik
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.
A J
AJ
Bilotta
Department of Pathology, Microbiology, and Immunology, Nashville, TN, USA.
M K
MK
Washington
Department of Pathology, Microbiology, and Immunology, Nashville, TN, USA.
F L
FL
Revetta
Department of Surgery, Division of Surgical Oncology, Nashville, TN, USA.
J J
JJ
Smith
Department of Biostatistics, Nashville, TN, USA.
X
X
Chen
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Vanderbilt Ingram Cancer Center, Nashville, TN, USA.|Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA.
K T
KT
Wilson
Vanderbilt Ingram Cancer Center, Nashville, TN, USA.|Department of Biochemistry, Nashville, TN, USA.
S W
SW
Hiebert
Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Vanderbilt Ingram Cancer Center, Nashville, TN, USA.|Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA.
C S
CS
Williams
D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
C110408:CBFA2T2 myeloid-transforming gene-related protein; C115744:CBFA2T3 protein, human; C117411:Cbfa2t3 protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins