An oncogenic role of eIF3e/INT6 in human breast cancer

Abstract

Altered expression of the eukaryotic translation initiation factor 3 (eIF3) subunit eIF3e/INT6 has been described in various types of human cancer, but the nature of its involvement in tumorigenesis is not yet clear. Using immunohistochemical analysis of 81 primary breast cancers, we found that high tumor grade correlated significantly with elevated cytoplasmic eIF3e level in epithelial tumor cells. Analysis of protein synthesis after siRNA-mediated knockdown in breast cancer cell lines indicated that eIF3e is not required for bulk translation. Microarray analysis of total and polysomal RNAs nonetheless identified distinct sets of mRNAs regulated either positively or negatively by eIF3e; functional classification of these revealed a marked enrichment of genes involved in cell proliferation, invasion and apoptosis. Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Finally, eIF3e-depleted breast carcinoma cells showed reduced in vitro invasion and proliferation. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. It regulates the translation, and in some cases abundance, of mRNAs involved in key aspects of cancer cell biology.

Expression of Truncated Eukaryotic Initiation Factor 3e (eIF3e) Resulting from Integration of Mouse Mammary Tumor Virus (MMTV) Causes a Shift from Cap-dependent to Cap-independent Translation

“…Early reports described decreased expression of eIF3e in breast (54) and non-small cell lung (54, 55) carcinomas. More recently, elevated eIF3e expression was correlated with high tumor grade in primary breast carcinomas (56). In the current study, changes in the translation of mRNA subsets was observed, some of which encode proteins involved in apoptosis and mitotic regulation.…”

INT6 interacts with MIF4GD/SLIP1 and is necessary for efficient histone mRNA translation

“…In the eIF3 complex, some subunits are essential, probably mainly the a, b, and c subunits, but others are likely to play a role in the translation of specific mRNAs or to allow specific regulations. Despite characterization of an interaction of INT6 with eIF4G (LeFebvre et al 2006) and its requirement for reconstitution from baculovirusexpressed subunits of a minimal complex allowing binding of the 48S on the initiation codon (Masutani et al 2007), several studies have ruled out a role of the protein for bulk translation (Bandyopadhyay et al 2000;Zhou et al 2005;Grzmil et al 2010). Indeed, it has been reported that deletion of the gene in fission yeast does not affect general translation or a polysome profile (Zhou et al 2005).…”

“…This activity is correlated with the ability of INT6 to interact with specific NMD factors like UPF1 and UPF2. It has also been recently reported that INT6 was able to act positively or negatively on the translation of specific mRNAs as evaluated by their presence in high-molecular-weight polysomes (Grzmil et al 2010). From these various observations, the picture emerges that INT6 selectively acts on translation in either a positive or negative way (Grzmil et al 2010), but the exact underlying molecular mechanisms remain to be characterized.…”

“…In line with such interactions, INT6 has been reported to control the stability of specific cellular proteins. Indeed, we and others have previously shown that it acts positively on the stability of the MCM7 subunit of the DNA replication licensing factor MCM by interacting with its polyubiquitinylated forms (Buchsbaum et al 2007;Grzmil et al 2010). Conversely, Chen et al (2007Chen et al ( , 2010 have shown that INT6, by binding to HIF-2a, triggers its proteolytic degradation.…”

“…Besides these activities on protein stability, INT6 has also been shown to intervene in translation; however, its effect seems restricted to specific proteins. Indeed, both in fission yeast and in mammalian cells, knockdown of INT6 does not appear to modify significantly incorporation of 35 S-labeled methionine in proteins or polysome profile (Bandyopadhyay et al 2000;Zhou et al 2005;Grzmil et al 2010). This has been reported by different groups and corresponds to our own observations.…”