Exo70 is transcriptionally up-regulated by hepatic nuclear factor 4α and contributes to cell cycle control in hepatoma cells.
Exo70 is transcriptionally up-regulated by hepatic nuclear factor 4α and contributes to cell cycle control in hepatoma cells.
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Exo70 通过肝核因子 4α 进行转录上调，有助于肝癌细胞的细胞周期控制
DOI：
10.18632/oncotarget.7133
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发表时间：
2016-02-23
期刊：
影响因子：
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通讯作者：
Zhan YY
中科院分区：
文献类型：
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作者：
Zhao Y;Hou J;Mi P;Mao L;Xu L;Zhang Y;Xiao L;Cao H;Zhang W;Zhang B;Song G;Hu T;Zhan YY
Exo 70是胞外膜复合物的一员，参与细胞胞吐、迁移、侵袭和自噬。然而，Exo 70在肝细胞癌中的表达调控和功能仍知之甚少。在本研究中，我们发现，在人肝癌细胞中，敲低肝核因子4α（HNF 4 α）后，Exo 70的表达显著降低，HNF 4 α是肝脏中最重要和最丰富的转录因子。这种调控发生在转录水平，而不是翻译后水平。HNF 4 α通过直接与Exo 70启动子中的HNF 4 α-反应元件结合来反式激活该启动子。细胞周期分析进一步显示HNF 4 α和Exo 70的下调是小檗碱诱导肝癌细胞G2/M期阻滞的关键。此外，敲低Exo 70或HNF 4 α均诱导肝癌细胞发生G2/M期阻滞。Exo 70在HNF 4 α下游通过增加Cdc 2表达促进G2/M期转换。总之，我们的研究结果表明Exo 70是HNF 4 α促进肝癌细胞周期进程的一个新的转录靶点，从而为肝癌治疗策略的开发提供了基础。
Exo70, a member of the exocyst complex, is involved in cell exocytosis, migration, invasion and autophagy. However, the expression regulation and function of Exo70 in hepatocellular carcinoma are still poorly understood. In this study, we found Exo70 expression in human hepatoma cells was greatly reduced after knocking down hepatic nuclear factor 4α (HNF4α), the most important and abundant transcription factor in liver. This regulation occurred at the transcriptional level but not post-translational level. HNF4α transactivated Exo70 promoter through directly binding to the HNF4α-response element in this promoter. Cell cycle analysis further revealed that down-regulation of HNF4α and Exo70 was essential to berberine-stimulated G2/M cell cycle arrest in hepatoma cells. Moreover, knocking down either Exo70 or HNF4α induced G2/M phase arrest of hepatoma cells. Exo70 acted downstream of HNF4α to stimulate G2/M transition via increasing Cdc2 expression. Together, our results identify Exo70 as a novel transcriptional target of HNF4α to promote cell cycle progression in hepatoma, thus provide a basis for the development of therapeutic strategies for hepatocellular carcinoma.