Novel HDAC5-interacting motifs of Tbx3 are essential for the suppression of E-cadherin expression and for the promotion of metastasis in hepatocellular carcinoma.
Novel HDAC5-interacting motifs of Tbx3 are essential for the suppression of E-cadherin expression and for the promotion of metastasis in hepatocellular carcinoma.
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Tbx3 的新型 HDAC5 相互作用基序对于抑制 E-钙粘蛋白表达和促进肝细胞癌转移至关重要
DOI：
10.1038/s41392-018-0025-6
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发表时间：
2018
影响因子：
39.3
通讯作者：
He ML
中科院分区：
文献类型：
--
作者：
Dong L;Dong Q;Chen Y;Li Y;Zhang B;Zhou F;Lyu X;Chen GG;Lai P;Kung HF;He ML
Tbx 3是一种转录抑制因子，在脊椎动物的器官发生、干细胞的自我更新和分化以及多种肿瘤的发生中是必不可少的。然而，Tbx 3参与肝细胞癌（HCC）转移的机制仍不清楚。在这项研究中，我们发现Tbx 3在临床HCC样本中显著上调，并且Tbx 3的表达升高促进了癌症进展。为了确定潜在的机制，进行系统的甘氨酸扫描诱变和缺失测定。我们确定了两个关键的基序，585 LFSYPYT 591和604 HRH 606，有助于抑制转录活性。这些基序也是Tbx 3通过抑制E-钙粘蛋白表达在体外和体内促进细胞迁移和转移所必需的。更重要的是，Tbx 3通过这些基序直接与HDAC 5相互作用，HDAC抑制剂阻断Tbx 3介导的细胞迁移和HCC中E-钙粘蛋白的下调。由于Tbx 3参与多种类型人类癌症的致癌作用，我们的研究结果表明，它是抗癌药物开发的重要靶点。抑制基因活性的调节蛋白与参与染色体重塑的酶相互作用，以促进肝癌细胞的迁移和转移。来自香港城市大学的Ming-Liang He及其同事发现，在肝脏肿瘤的组织活检中，T-box转录因子Tbx 3的水平显着增加。他们将表达Tbx 3的人类肝癌细胞注射到小鼠体内，发现Tbx 3活性与癌症进展之间呈正相关。通过突变和删除Tbx 3的部分，研究人员确定了结合组蛋白去乙酰化酶5的两个特定片段，组蛋白去乙酰化酶5是一种参与确保DNA卷曲的酶，被紧紧缠绕以抑制基因活性。这种相互作用是Tbx 3的肿瘤促进功能所必需的，并且可以用药物靶向，以防止侵袭性肝癌患者的转移。
Tbx3, a transcriptional repressor, is essential in the organogenesis of vertebrates, stem cell self-renewal and differentiation, and the carcinogenesis of multiple tumor types. However, the mechanism by which Tbx3 participates in the metastasis of hepatocellular carcinoma (HCC) remains largely unknown. In this study, we show that Tbx3 was dramatically upregulated in clinical HCC samples and that elevated expression of Tbx3 promoted cancer progression. To determine the underlying mechanism, systematic glycine scan mutagenesis and deletion assays were performed. We identified two critical motifs, 585LFSYPYT591 and 604HRH606, that contribute to the repression of transcriptional activity. These motifs are also essential for Tbx3 to promote cell migration and metastasis both in vitro and in vivo via the suppression of E-cadherin expression. More importantly, Tbx3 directly interacts with HDAC5 via these motifs, and an HDAC inhibitor blocks Tbx3-mediated cell migration and the downregulation of E-cadherin in HCC. As Tbx3 is involved in the carcinogenesis of multiple types of human cancers, our findings suggest an important target for anti-cancer drug development. A regulatory protein that represses gene activity interacts with an enzyme involved in chromosome remodeling to promote the migration and metastasis of liver cancer cells. Ming-Liang He from the City University of Hong Kong and colleagues found that levels of the T-box transcription factor Tbx3 were dramatically increased in tissue biopsies of liver tumors. They injected Tbx3-expressing human liver cancer cells into mice and saw a positive correlation between Tbx3 activity and cancer progression. By mutating and deleting parts of Tbx3, the researchers identified two particular stretches of the protein that bind histone deacetylase 5, an enzyme involved in ensuring DNA coils, are wound tight to suppress gene activity. This interaction is needed for Tbx3’s tumor-promoting function and may be targetable with drugs in order to prevent metastasis in patients with aggressive liver cancer.
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影响因子：
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作者：
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