Abstract

PurposeBoth chemokine receptors (CXCR) 7 and 4 are known to be involved in a vast array of pathological events in the development cancer. However, it is not yet known whether the CXCR7/CXCR4 heterodimer can form in vivo, and if it does, the functional difference between CXCR7 monomer and the CXCR7/CXCR4 heterodimer.Experimental DesignThe expression of two CXCRs, CXCR7/CXCR4 heterodimer and histone demethylase JMJD2A in human colorectal rectal cancer (CRC) tissue was detected by western blot and immunohistochemistry. We then studied the role of the CXCR7/CXCR4 heterodimer in CRC tumorigenesis in Villin‐CXCR7‐CXCR4 transgenic mice and APCMin/+/villin‐CXCR7‐CXCR4 mice.ResultsCXCR 7 and 4 can form heterodimers in vivo and promote colorectal tumorigenesis through histone demethylation. Compared with adjacent non‐neoplastic tissue, human colorectal rectal cancer (CRC) tissue showed a significantly higher expression of CXCR4 and CXCR7, which was co‐localized in the cancer cell epithelium. CXCR/CXCR4 heterodimerization was associated with increased histone demethylase JMJD2A. Villin‐CXCR7‐CXCR4 transgenic mice presented a greater degree of exacerbated colitis and tumorigenesis than villin‐CXCR7 and villin‐CXCR4 mice. The CXCR7/CXCR4 heterodimer also increased APC mutation‐driven colorectal tumorigenesis in APCMin/+/villin‐CXCR7‐CXCR4 mice. Further analysis showed that the CXCR7/CXCR4 heterodimer induced nuclear β‐arrestin 1 recruitment and histone demethylase JMJD2A, leading to histone demethylation and increased transcription of inflammatory factors and oncogenes.ConclusionOur data reveal a novel mechanism of colorectal tumorigenesis through CXCR7/CXCR4 heterodimer‐induced histone demethylation. Inhibition of CXCR7/CXCR4 heterodimer‐induced histone demethylation could be an effective strategy for cancer treatment.Support or Funding InformationThis work was supported by Natural Science Foundation of China (91629303) The graphical abstractimageThe graphical abstractThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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