Methylation of the Promoter Region of the Tight Junction Protein-1 by DNMT1 Induces EMT-like Features in Multiple Myeloma.
Methylation of the Promoter Region of the Tight Junction Protein-1 by DNMT1 Induces EMT-like Features in Multiple Myeloma.
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DOI：
10.1016/j.omto.2020.10.004
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发表时间：
2020-12-16
期刊：
影响因子：
--
通讯作者：
Zhang XD
中科院分区：
文献类型：
--
作者：
Li M;Qi L;Xu JB;Zhong LY;Chan S;Chen SN;Shao XR;Zheng LY;Dong ZX;Fang TL;Mai ZY;Li J;Zheng Y;Zhang XD
引发多发性骨髓瘤（MM）发展的分子改变尚不完全清楚。我们的研究结果显示，TJP1在MM中下调，并与癌症基因组图谱（TCGA）数据库和患者样本中MM患者的总体生存率呈正相关。与此同时，与健康样本相比，MM患者中代表MM转移的细胞粘附能力下降，同时MM细胞的上皮-间质转化（EMT）转录样模式显著激活。进一步的分析表明，TJP1负向调节EMT，从而正向调节来自TCGA数据库的MM和MM1s细胞的细胞粘附。此外，TJP1启动子上各CpG位点的甲基化水平与TJP1表达水平呈负相关。实时荧光定量PCR和western blot检测表明，甲基化酶DNMT1调控TJP1的甲基化。最后，MM临床药物硼替佐米、甲基化抑制剂或TJP1过表达联合治疗可显著抑制MM原位模型肿瘤细胞的活力和进展。综上所述，我们的研究结果表明，DNMT1促进TJP1启动子的甲基化，从而降低其表达并调节emt抑制MM细胞粘附的发展。因此，TJP1的甲基化是预防MM疾病进展的潜在治疗剂。我们证明DNA甲基转移酶有助于DNMT1下调TJP1，从而随后促进emt介导的MM进展和BM微环境的发展，导致MM转移。我们相信TJP1表达和甲基转移酶抑制剂将促进硼替佐米联合治疗的临床实践。
The molecular alterations that initiate the development of multiple myeloma (MM) are not fully understood. Our results revealed that TJP1 was downregulated in MM and positively related to the overall survival of MM patients in The Cancer Genome Atlas (TCGA) database and patient samples. In parallel, cell adhesion capacity representing MM metastasis was decreased in MM patients compared with healthy samples, together with the significantly activated epithelial-to-mesenchymal transition (EMT) transcriptional-like patterns of MM cells. Further analyses demonstrated that TJP1 negatively regulated EMT and consequently positively regulated cell adhesion in MM from TCGA database and MM1s cells. Furthermore, the methylation level of each CpG site on the TJP1 promoter was negatively correlated with TJP1 expression levels. Quantitative real-time PCR and western blot assays demonstrated that methylase DNMT1 regulated the methylation of TJP1. Finally, treatment with a combination of the MM clinical medicine bortezomib, methylation inhibitor, or TJP1 overexpression significantly suppressed the viability and progression of tumor cells of MM orthotopic models. In summary, our results indicate that DNMT1 promotes the methylation of TJP1 promoter, thereby decreasing its expression and regulating the development of EMT-inhibited MM cell adhesion. Therefore, methylation of TJP1 is a potential therapeutic agent to prevent the progression of MM disease. We demonstrate that DNA methyltransferases contribute to the downregulation of TJP1 by DNMT1, thus subsequently promoting the development of EMT-mediated MM progression and the BM microenvironment, leading to MM metastasis. We believe that TJP1 expression and methyltransferase inhibitors would facilitate therapies combined with bortezomib in clinical practice.
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作者：
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影响因子：
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作者：
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作者：
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影响因子：
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作者：
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DOI：
10.18632/oncoscience.356
发表时间：
2017-07
期刊：
Oncoscience
影响因子：
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作者：
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通讯作者：
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