Abstract
Both chemokine receptors (CXCRs) 7 and 4 can facilitate immune cell migration and mediate a vast array of physiological and pathological events. Herein we report, in both human and animal studies, that these two CXCRs can form heterodimers in vivo and promote colorectal tumorigenesis through histone demethylation. Compared with adjacent non-neoplastic tissue, human colorectal cancer (CRC) tissue showed a significant higher expression of CXCR4 and CXCR7, which was colocalized in the cancer cell epithelium. The CXCR/CXCR4 heterodimerization was associated with increased histone demethylase JMJD2A. Villin-CXCR7-CXCR4 transgenic mice demonstrated a greater degree of exacerbated colitis and tumorigenesis than villin-CXCR7 and villin-CXCR4 mice. The CXCR7/CXCR4 heterodimerization also promoted APC mutation-driven colorectal tumorigenesis in APCMin/+/villin-CXCR7-CXCR4 mice. Further analysis showed that the CXCR7/CXCR4 heterodimer induced nuclear βarr1 recruitment and histone demethylase JMJD2A, leading to histone demethylation and resulting in transcription of inflammatory factors and oncogenes. This study uncovered a novel mechanism of colorectal tumorigenesis through the CXCR7/CXCR4 heterodimer-induced histone demethylation. Inhibition of CXCR7/CXCR4 heterodimer-induced histone demethylation could be an effective strategy for the prevention and treatment of colorectal cancer.
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Change history
10 June 2019
A correction to this paper has been published and can be accessed via a link at the top of the paper.
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Acknowledgements
This work was supported by Natural Science Foundation of China (81673449 and 91629303) and Beijing Natural Science Foundation Program and Scientific Research Program of Municipal Commission of Education (KZ201710025020 and KZ201810025033).
Author contributions
X-JQ conceived and designed the study. Z-YS and FW performed experiments. Z-YS wrote the manuscript. S-XC performed statistical analysis. Z-HG provided intellectual inputs and edited the manuscript.
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Song, ZY., Wang, F., Cui, SX. et al. CXCR7/CXCR4 heterodimer-induced histone demethylation: a new mechanism of colorectal tumorigenesis. Oncogene 38, 1560–1575 (2019). https://doi.org/10.1038/s41388-018-0519-2
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DOI: https://doi.org/10.1038/s41388-018-0519-2
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