CXCR7/CXCR4 heterodimer-induced histone demethylation: a new mechanism of colorectal tumorigenesis
CXCR7/CXCR4 heterodimer-induced histone demethylation: a new mechanism of colorectal tumorigenesis
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CXCR7/CXCR4异二聚体诱导的组蛋白去甲基化：结直肠肿瘤发生的新机制
DOI：
10.1038/s41388-018-0519-2
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发表时间：
2019-02-28
期刊：
影响因子：
8
通讯作者：
Qu, Xian-Jun
中科院分区：
文献类型：
--
作者：
Song, Zhi-Yu;Wang, Feng;Qu, Xian-Jun
趋化因子受体 (CXCR) 7 和 4 都可以促进免疫细胞迁移并介导大量的生理和病理事件。在此，我们在人类和动物研究中报告，这两种 CXCR 可以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的发生。与邻近的非肿瘤组织相比，人结直肠癌（CRC）组织表现出 CXCR4 和 CXCR7 的表达显着较高，它们共定位于癌细胞上皮中。 CXCR/CXCR4 异二聚化与组蛋白去甲基化酶 JMJD2A 的增加相关。与villin-CXCR7和villin-CXCR4小鼠相比，Villin-CXCR7-CXCR4转基因小鼠表现出更大程度的结肠炎和肿瘤发生加剧。 CXCR7/CXCR4 异二聚化还促进 APCmin/+/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化酶JMJD2A，导致组蛋白去甲基化并导致炎症因子和癌基因的转录。这项研究通过 CXCR7/CXCR4 异二聚体诱导的组蛋白去甲基化揭示了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。
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 promotedAPCmutation-driven colorectal tumorigenesis inAPCMin/+/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.