Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou, China.
Oncogene. 2019 Feb;38(9):1560-1575. doi: 10.1038/s41388-018-0519-2. Epub 2018 Oct 18.
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 APC/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.
趋化因子受体 (CXCRs) 7 和 4 均可促进免疫细胞迁移，并介导广泛的生理和病理事件。本研究在人体和动物研究中均报告称，这两种 CXCR 可在体内形成异二聚体，并通过组蛋白去甲基化促进结直肠肿瘤发生。与相邻的非肿瘤组织相比，人结直肠癌 (CRC) 组织中 CXCR4 和 CXCR7 的表达明显升高，且在癌细胞上皮中发生共定位。CXCR/CXCR4 异二聚化与组蛋白去甲基酶 JMJD2A 的增加有关。与 villin-CXCR7 和 villin-CXCR4 小鼠相比，villin-CXCR7-CXCR4 转基因小鼠表现出更严重的结肠炎和肿瘤恶化。CXCR7/CXCR4 异二聚化也促进了 APC/villin-CXCR7-CXCR4 小鼠中 APC 突变驱动的结直肠肿瘤发生。进一步分析表明，CXCR7/CXCR4 异二聚体诱导核 βarr1 募集和组蛋白去甲基酶 JMJD2A，导致组蛋白去甲基化，从而转录炎症因子和癌基因。本研究揭示了一种通过 CXCR7/CXCR4 异二聚体诱导组蛋白去甲基化促进结直肠肿瘤发生的新机制。抑制 CXCR7/CXCR4 异二聚体诱导的组蛋白去甲基化可能是预防和治疗结直肠癌的有效策略。
