Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, People's Republic of China.
Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
Am J Pathol. 2019 May;189(5):1065-1076. doi: 10.1016/j.ajpath.2019.01.010. Epub 2019 Feb 5.
It has been reported that disorders of epigenetic modulation play a critical role in carcinogenesis. Methyl-CpG binding domain protein 2 (MBD2) is known to act as an epigenetic modulator in various types of tumors; however, the role of MBD2 in lung adenocarcinoma (LUAD) remains unclear. Herein, we demonstrated the down-regulation of MBD2 in LUAD compared with adjacent nontumor tissues. The down-regulation of MBD2 in LUAD was correlated with metastasis and poor survival. In addition, MBD2 inhibited tumor metastasis by maintaining the expression of the miR-200s, which suppressed the invasive properties of tumors. Also, MBD2 positively correlated with 5-hydroxymethylcytosine content in the promoter of miR-200s. The conventional view is that MBD2 acts as a transcriptional suppressor. However, the data revealed that MBD2 may act as a transcriptional activator by recruiting 10 to 11 translocation 1 (TET1) and forming a chromatin-remodeling complex. The MBD2-TET1 complex locates to the TET1 promoter and removes the methyl residues in this region, thereby activating TET1 transcription. TET1 also acted as a tumor suppressor in LUAD. Taken together, the data demonstrate the correlation between MBD2, miR-200s, and TET1, and tumor suppressive effect of MBD2 through up-regulation of TET1 and the miR-200s.
据报道，表观遗传修饰失调在癌症发生中起着关键作用。甲基-CpG 结合域蛋白 2（MBD2）已知在各种类型的肿瘤中作为表观遗传调节剂起作用；然而，MBD2 在肺腺癌（LUAD）中的作用尚不清楚。在此，我们证明与相邻非肿瘤组织相比，MBD2 在 LUAD 中下调。MBD2 在 LUAD 中的下调与转移和预后不良相关。此外，MBD2 通过维持 miR-200s 的表达来抑制肿瘤转移，从而抑制肿瘤的侵袭特性。此外，MBD2 与 miR-200s 启动子中的 5-羟甲基胞嘧啶含量呈正相关。传统观点认为 MBD2 作为转录抑制因子起作用。然而，数据显示 MBD2 可能通过招募 10 到 11 易位 1（TET1）并形成染色质重塑复合物来充当转录激活剂。MBD2-TET1 复合物定位于 TET1 启动子并去除该区域中的甲基残基，从而激活 TET1 转录。TET1 也在 LUAD 中作为肿瘤抑制因子起作用。总之，数据表明 MBD2、miR-200s 和 TET1 之间存在相关性，并且 MBD2 通过上调 TET1 和 miR-200s 发挥肿瘤抑制作用。
