Li Yanping, Lin Athena W, Zhang Xiaojing, Wang Yanqing, Wang Xiaoling, Goodrich David W
Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cancer Res. 2007 Jul 15;67(14):6657-64. doi: 10.1158/0008-5472.CAN-06-3234.
The evolutionarily conserved TREX (Transcription/Export) complex physically couples transcription, messenger ribonucleoprotein particle biogenesis, RNA processing, and RNA export for a subset of genes. HPR1 encodes an essential component of the S. cerevisiae TREX complex. HPR1 loss compromises transcriptional elongation, nuclear RNA export, and genome stability. Yet, HPR1 is not required for yeast viability. Thoc1 is the recently discovered human functional orthologue of HPR1. Thoc1 is expressed at higher levels in breast cancer than in normal epithelia, and expression levels correlate with tumor size and metastatic potential. Depletion of Thoc1 protein (pThoc1) in human cancer cell lines compromises cell proliferation. It is currently unclear whether Thoc1 is essential for all mammalian cells or whether cancer cells may differ from normal cells in their dependence on Thoc1. To address this issue, we have compared the requirements for Thoc1 in the proliferation and survival of isogenic normal and oncogene-transformed cells. Neoplastic cells rapidly lose viability via apoptotic cell death on depletion of pThoc1. Induction of apoptotic cell death is coincident with increased DNA damage as indicated by the appearance of phosphorylated histone H2AX. In contrast, the viability of normal cells is largely unaffected by pThoc1 loss. Normal cells lacking Thoc1 cannot be transformed by forced expression of E1A and Ha-ras, suggesting that Thoc1 may be important for neoplastic transformation. In sum, our data are consistent with the hypothesis that cancer cells require higher levels of pThoc1 for survival than normal cells. If true, pThoc1 may provide a novel molecular target for cancer therapy.
进化上保守的TREX（转录/输出）复合体在物理上耦合了一部分基因的转录、信使核糖核蛋白颗粒生物合成、RNA加工和RNA输出。HPR1编码酿酒酵母TREX复合体的一个必需组分。HPR1的缺失会损害转录延伸、核RNA输出及基因组稳定性。然而，酵母的生存并不需要HPR1。Thoc1是最近发现的HPR1的人类功能同源物。Thoc1在乳腺癌中的表达水平高于正常上皮组织，且表达水平与肿瘤大小和转移潜力相关。在人类癌细胞系中敲低Thoc1蛋白（pThoc1）会损害细胞增殖。目前尚不清楚Thoc1对所有哺乳动物细胞是否必需，或者癌细胞在对Thoc1的依赖性上是否可能与正常细胞不同。为解决这个问题，我们比较了等基因正常细胞和癌基因转化细胞在增殖和存活过程中对Thoc1的需求。在敲低pThoc1后，肿瘤细胞通过凋亡性细胞死亡迅速丧失活力。如磷酸化组蛋白H2AX的出现所示，凋亡性细胞死亡的诱导与DNA损伤增加同时发生。相比之下，正常细胞的活力在很大程度上不受pThoc1缺失的影响。缺乏Thoc1的正常细胞不能通过强制表达E1A和Ha-ras进行转化，这表明Thoc1可能对肿瘤转化很重要。总之，我们的数据与癌细胞比正常细胞需要更高水平的pThoc1来维持生存这一假设一致。如果这是真的，pThoc1可能为癌症治疗提供一个新的分子靶点。
