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Abstract
The tumor-infiltrating Tregs are linked to colorectal cancer progression and outcome. FOXP3 is regarded as a critical developmental and functional factor for Tregs. FOXP3-TSDR demethylation is required for stable expression of FOXP3 and maintenance of Treg function. In our study, we found specific DNA hypomethylation of FOXP3-TSDR in CD4+ T cells from colon tumor tissues as compared with normal colonic tissues. Moreover, we also found that the expression of STAT5 and TET2 was increased in CD4+ T cells from colon tumor tissues, and the superfluous STAT5 and TET2 binding to FOXP3-TSDR resulted in DNA hypomethylation. In conclusion, we have demonstrated that excessive amounts of STAT5 may bind more TET2 to the FOXP3-TSDR and upregulate FOXP3 expression via DNA demethylation. Our study improved the mechanism of FOXP3-TSDR hypomethylation in tumor-infiltrating CD4+ T cells of CRC patients.
Highlights
Colorectal cancer (CRC) is the development of cancer in the colon or rectum
We provided evidences indicating that overexpressed STAT5 combines with TET2 to form complexes that bind to the forkhead box P3 (FOXP3)-Treg-specific demethylated region (TSDR), resulting in excessive demethylation in tumor-infiltrating CD4+ T cells
Our results suggest that the abnormally reduced Foxp3-TSDR methylation may be an important factor to increase the expression of FOXP3 in CD4+ T cells of CRC patients
Summary
Colorectal cancer (CRC) is the development of cancer in the colon or rectum. It is one of the most common fatal malignancies in the world; globally, more than 1 million people get colorectal cancer every year [1]. The transcription factor forkhead box P3 (FOXP3) is a subfamily member of forkhead transcription factor, which is expressed in CD4+CD25+ Tregs, and it is regarded as a critical developmental and functional factor for Tregs [5]. Treg-specific demethylated region (TSDR) is a CpG dinucleotide-rich and highly conserved region within the conserved noncoding sequences 2 (CNS2) at the FOXP3 locus [6]. TSDR demethylation is necessary for stable FOXP3 expression and maintenance of the suppressive phenotype for nTregs [7]
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