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首页> 外文期刊>Gastroenterology >Histone Demethylase JMJD2D Interacts With beta-Catenin to Induce Transcription and Activate Colorectal Cancer Cell Proliferation and Tumor Growth in Mice
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Histone Demethylase JMJD2D Interacts With beta-Catenin to Induce Transcription and Activate Colorectal Cancer Cell Proliferation and Tumor Growth in Mice

机译：组蛋白脱甲基酶JMJD2D与β-catenin相互作用以诱导转录和激活直肠癌细胞增殖和小鼠肿瘤生长

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摘要

BACKGROUND & AIMS: Wnt signaling contributes to the development of colorectal cancer (CRC). We studied interactions between lysine demethylase 4D (KDM4D or JMJD2D) and b-catenin, a mediator of Wnt signaling, in CRC cell lines and the effects on tumor formation in mice. METHODS: We obtained colorectal tumor specimens and surrounding nontumor colon tissues (controls) from patients undergoing surgery in China; levels of JMJD2D were measured by immunohistochemical or immunoblot analysis. JMJD2D expression was knocked down in CRC (CT26, HCT116, and SW480 cells) using small hairpin RNAs, and cells were analyzed with viability, flow cytometry, colony formation, and transwell migration and invasion assays. Cells were also grown as tumor xenografts in nude mice or injected into tail veins or spleens of mice, and metastases were measured. We performed promoter activity, co-immunoprecipitation, and chromatin immunoprecipitation assays. We also performed studies with Apcmin/thorn and JMJD2D-knockout mice; these mice were crossed, and colorectal tumor formation in offspring (Apcmin/thorn Jmjd2d thorn/thorn and Apcmin/thorn Jmjd2d-/-) was analyzed. JMJD2D-knockout and wild-type (control) mice were given azoxymethane followed by dextran sodium sulfate to induce colitis-associated CRC; some mice were given the JMJD2D inhibitor 5-chloro-8-hydroxyquinoline (5-c-8HQ) or vehicle to examine the effects of 5-c-8HQ on intestinal tumor formation. RESULTS: Levels of JMJD2D were significantly higher in human colorectal tumors than in control tissues and correlated with levels of proliferating cell nuclear antigen. JMJD2D knockdown reduced CRC cell proliferation, migration, and invasion, as well as growth of xenograft tumors and formation of metastases in mice. JMJD2D was required for expression of b-catenin in CRC cell lines; ectopic expression of JMJD2D increased the promoter activities of genes regulated by b-catenin (MYC, CCND1, MMP2, and MMP9). We found that JMJD2D and b-catenin interacted physically and that JMJD2D demethylated H3K9me3 at promoters of b-catenin target genes. JMJD2D-knockout mice developed fewer colitis-associated colorectal tumors than control mice, and their tumor tissues had lower levels of b-catenin, MYC, cyclin D1, and proliferating cell nuclear antigen than tumors from control mice. Apcmin/thorn Jmjd2d-/-mice developed fewer and smaller colon tumors than Apcmin/thorn mice. Mice given 5-c-8HQ developed smaller and fewer colitisassociated tumors, with lower levels of cell proliferation, than mice given vehicle. Apcmin/thorn mice given 5-c-8HQ also developed fewer tumors in intestines and colons than mice given vehicle. CONCLUSIONS: Levels of the histone demethylase JMJD2D are increased in human colorectal tumors compared with nontumor colon tissues. JMJD2D interacts with b-catenin to activate transcription of its target genes and promote CRC cell proliferation, migration, and invasion, as well as formation of colorectal tumors in mice.
机译：背景和目的：WNT信号传导有助于结直肠癌（CRC）。我们在CRC细胞系中研究了赖氨酸脱甲基酶4D（KDM4D或JMJD2D）和B-Catenin，WNT信号传导的介体和对小鼠肿瘤形成的影响。方法：我们从中国接受手术的患者中获得结直肠肿瘤标本和周围的Nontumor结肠组织（对照）;通过免疫组织化学或免疫印迹分析测量JMJD2D的水平。使用小型发夹RNA在CRC（CT26，HCT116和SW480细胞中）敲击JMJD2D表达，并用活力，流式细胞术，菌落形成和Transwell迁移和侵袭测定分析细胞。细胞也被生长为裸鼠中的肿瘤异种移植物，或者注射到小鼠的尾静脉或脾脏，并测量转移。我们进行启动子活性，共免疫沉淀和染色质免疫沉淀测定。我们还用APCMIN / Thorn和JMJD2D-Knokeout小鼠进行了研究;分析了这些小鼠的交叉，分析了后代的结直肠肿瘤形成（APCMIN / Thorn JMJD2D刺/刺和Apcmin / Thorn JMJD2D-/ - ）。将JMJD2D-kextut和野生型（对照）小鼠给予氮氧基甲烷，然后被葡聚糖硫酸钠诱导结肠炎相关的CRC;将一些小鼠赋予JMJD2D抑制剂5-氯-8-羟基喹啉（5-C-8HQ）或载体，以检查5-C-8HQ对肠肿瘤形成的影响。结果：人结肠直肠肿瘤的JMJD2D水平显着高于对照组织，与增殖细胞核抗原水平相关。 JMJD2D敲低降低CRC细胞增殖，迁移和侵袭，以及异种移植肿瘤的生长以及小鼠中转移的形成。 JMJD2D是在CRC细胞系中表达B-Catenin的表达; JMJD2D的异位表达增加了B-Catenin（MYC，CCND1，MMP2和MMP9）调节的基因的启动子活性。我们发现JMJD2D和B-Catenin在物理上和JMJD2D去甲基化H3K9ME3在B-Catenin靶基因的启动子上进行了相互作用。 JMJD2D-Knockout小鼠的小鼠显得较少的结肠炎相关的结肠直肠肿瘤，而不是对照小鼠，并且它们的肿瘤组织具有较低水平的B-Catenin，MyC，Cyclin D1和增殖细胞核抗原，而不是对照小鼠的肿瘤。 APCMIN / Thorn JMJD2D - / - 小鼠比Apcmin / Thorn小鼠产生的较少和较小的结肠肿瘤。给定5-C-8HQ的小鼠显影性较少，更少的结肠炎病变肿瘤，细胞增殖水平较低，比给定载体的小鼠。给定5-C-8HQ的APCMIN /刺小鼠也在肠道中产生较少的肿瘤，而且小鼠比给予车辆的小鼠。结论：与不源结肠组织相比，组蛋白脱甲基酶JMJD2D的水平增加。 JMJD2D与B-Catenin相互作用以激活其靶基因的转录，促进CRC细胞增殖，迁移和侵袭，以及在小鼠中形成结肠直肠癌。

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  • 来源
    《Gastroenterology》 |2019年第4期|共15页
  • 作者

    Peng Kesong; Kou Lele; Yu Li; Bai Chaonan; Li Ming; Mo Pingli; Li Wengang; Yu Chundong;

  • 作者单位

    Xiamen Univ Sch Life Sci Innovat Ctr Cell Biol State Key Lab Cellular Stress Biol Xiamen 361102;

    Xiamen Univ Sch Life Sci Innovat Ctr Cell Biol State Key Lab Cellular Stress Biol Xiamen 361102;

    Xiamen Univ Sch Life Sci Innovat Ctr Cell Biol State Key Lab Cellular Stress Biol Xiamen 361102;

    Xiamen Univ Sch Life Sci Innovat Ctr Cell Biol State Key Lab Cellular Stress Biol Xiamen 361102;

    Xiamen Univ Xiangan Hosp Hepatobiliary &

    Pancreat &

    Organ Transplantat Sur Xiamen Peoples R;

    Xiamen Univ Sch Life Sci Innovat Ctr Cell Biol State Key Lab Cellular Stress Biol Xiamen 361102;

    Xiamen Univ Xiangan Hosp Hepatobiliary &

    Pancreat &

    Organ Transplantat Sur Xiamen Peoples R;

    Xiamen Univ Sch Life Sci Innovat Ctr Cell Biol State Key Lab Cellular Stress Biol Xiamen 361102;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 消化系及腹部疾病;
  • 关键词

    PCNA; Mouse Model; Colon Cancer; Gene Regulation;

    机译：PCNA;小鼠模型;结肠癌;基因调节;

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