Underexpressed coactivators PGC1 α and SRC1 impair hepatocyte nuclear factor 4α function and promote dedifferentiation in human hepatoma cells
Underexpressed coactivators PGC1 α and SRC1 impair hepatocyte nuclear factor 4α function and promote dedifferentiation in human hepatoma cells
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DOI：
10.1074/jbc.m604046200
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发表时间：
2006-10-06
影响因子：
4.8
通讯作者：
Jover, Ramiro
中科院分区：
文献类型：
--
作者：
Martinez-Jimenez, Celia P.;Gomez-Lechon, M. Jose;Jover, Ramiro
肝细胞核因子4α(HNF4α)在肝脏发育过程中起重要作用，在成人肝脏中对多种肝基因的转录调控起着重要作用。在这里，我们已经证明，在人肝癌HepG2细胞中，HNF4α的表达水平与人肝脏一样高，但其对靶基因的活性非常低或缺失。我们发现HNF4α的低表达可能是HNF4α在HepG2细胞中功能缺失的原因之一。其中，以APOCIII启动子为启动子的Pgc1α和SRc1是两个最重要的HNF4α共激活因子。此外，这两个共激活因子的表达在所有被研究的人肝癌中都被下调。重组腺病毒过表达SRC1和PGC1α导致HNF4α依赖基因(APOCIII、ApoAV、PEPCK、AldoB、OTC和CYP7A1)显著上调，并迫使HepG2细胞向更分化的表型转变，这表现为尿毒率增加。前列环素α的积极作用依赖于HNF4α。最后，人肝细胞和HepG2细胞的胰岛素处理导致PGC1α的抑制，以及伴随而来的APOCIII、PEPCK、AldoB和OTC的下调。总之，我们的结果表明，SRC1，特别是PGC1α，对于HNF4α在人肝脏中的正常功能以及对参与代谢和动态平衡的多个肝脏基因的整合控制是关键的辅助激活因子。关键的HNF4α共激活因子的下调可能是人肝癌去分化的决定因素。
Hepatocyte nuclear factor 4 alpha ( HNF4 alpha) plays critical roles during liver development and in the transcriptional regulation of many hepatic genes in adult liver. Here we have demonstrated that in human hepatoma HepG2 cells, HNF4 alpha is expressed at levels as high as in human liver but its activity on target genes is very low or absent. We have discovered that the low expression of key coactivators ( PGC1 alpha, SRC1, SRC2, and PCAF) might account for the lack of function of HNF4 alpha in HepG2 cells. Among them, PGC1 alpha and SRC1 are the two most important HNF4 alpha coactivators as revealed by reporter assays with an ApoCIII promoter construct. Moreover, the expression of these two coactivators was found to be down- regulated in all human hepatomas investigated. Overexpression of SRC1 and PGC1 alpha by recombinant adenoviruses led to a significant up- regulation of well characterized HNF4 alpha - dependent genes ( ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. The positive effect of PGC1 alpha was seen to be dependent on HNF4 alpha. Finally, insulin treatment of human hepatocytes and HepG2 cells caused repression of PGC1 alpha and a concomitant down- regulation of ApoCIII, PEPCK, AldoB, and OTC. Altogether, our results suggest that SRC1, and notably PGC1 alpha, are key coactivators for the proper function of HNF4 alpha in human liver and for an integrative control of multiple hepatic genes involved in metabolism and homeostasis. The down- regulation of key HNF4 alpha coactivators could be a determinant factor for the dedifferentiation of human hepatomas.