Data from Cancer Cells and Normal Cells Differ in Their Requirements for <i>Thoc1</i>

Abstract

<div>Abstract<p>The evolutionarily conserved TREX (<i>Tr</i>anscription/<i>Ex</i>port) complex physically couples transcription, messenger ribonucleoprotein particle biogenesis, RNA processing, and RNA export for a subset of genes. <i>HPR1</i> encodes an essential component of the <i>S. cerevisiae</i> TREX complex. <i>HPR1</i> loss compromises transcriptional elongation, nuclear RNA export, and genome stability. Yet, <i>HPR1</i> is not required for yeast viability. <i>Thoc1</i> is the recently discovered human functional orthologue of <i>HPR1. Thoc1</i> is expressed at higher levels in breast cancer than in normal epithelia, and expression levels correlate with tumor size and metastatic potential. Depletion of <i>Thoc1</i> protein (pThoc1) in human cancer cell lines compromises cell proliferation. It is currently unclear whether <i>Thoc1</i> is essential for all mammalian cells or whether cancer cells may differ from normal cells in their dependence on <i>Thoc1</i>. To address this issue, we have compared the requirements for <i>Thoc1</i> 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 <i>Thoc1</i> cannot be transformed by forced expression of E1A and Ha-<i>ras</i>, suggesting that <i>Thoc1</i> 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. [Cancer Res 2007;67(14):6657–64]</p></div>