The Tumor Suppressive Role of eIF3f and Its Function in Translation Inhibition and rRNA Degradation

Abstract

Deregulated translation plays an important role in human cancer. We previously reported decreased eukaryotic initiation factor 3 subunit f (eIF3f) expression in pancreatic cancer. Whether decreased eIF3f expression can transform normal epithelial cells is not known. In our current study, we found evidence that stable knockdown of eIF3f in normal human pancreatic ductal epithelial cells increased cell size, nuclear pleomorphism, cytokinesis defects, cell proliferation, clonogenicity, apoptotic resistance, migration, and formation of 3-dimensional irregular masses. Our findings support the tumor suppressive role of eIF3f in pancreatic cancer. Mechanistically, we found that eIF3f inhibited both cap-dependent and cap-independent translation. An increase in the ribosomal RNA (rRNA) level was suggested to promote the generation of cancer. The regulatory mechanism of rRNA degradation in mammals is not well understood. We demonstrated here that eIF3f promotes rRNA degradation through direct interaction with heterogeneous nuclear ribonucleoprotein (hnRNP) K. We showed that hnRNP K is required for maintaining rRNA stability: under stress conditions, eIF3f dissociates hnRNP K from rRNA, thereby preventing it from protecting rRNA from degradation. We also demonstrated that rRNA degradation occurred in non-P body, non-stress granule cytoplasmic foci that contain eIF3f. Our findings established a new mechanism of rRNA decay regulation mediated by hnRNP K/eIF3f and suggest that the tumor suppressive function of eIF3f may link to impaired rRNA degradation and translation.

Translation factors and ribosomal proteins control tumor onset and progression: how?

“…120 However, eIF3f subunit can ultimately act as a tumor-suppressor-like molecule. 121 Moreover, these data demonstrate that ubiquitous factors of the translational machinery are highly specific for their tumorigenic potential in vivo. It has not been yet demonstrated that changes in eIF3 subunit levels alter the spectrum of the translated mRNAs.…”

The role of eIF3 and its individual subunits in cancer

“…Shi et al also noted that cells with high levels of 3f have reduced amounts of 60S ribosomes relative to 40S ribosomes, apparently caused by 28S rRNA degradation. In contrast, knockdown of 3f expression in stably transfected normal human pancreatic ductal epithelial cells stimulates both cap-dependent and IRES-dependent protein synthesis and cell proliferation, as well as other malignant phenotypes [40,114]. These findings imply that 3f acts to suppress eIF3 activity and protein synthesis, where loss of the subunit would appear to over-activate the initiation factor.…”

“…In a related study, the rabies virus M protein was found to bind to eIF3; this interaction results in inhibition of 5′-cap-dependent translation, but not IRESdependent internal initiation [39]. In contrast, the 3f subunit was shown to inhibit IRES-dependent translation [40]. However, it is not known whether eIF3 interactions with IRESs contribute to malignant transformation following changes in the level of one of its subunits.…”

“…CDK11p46 phosphorylates 3f at Ser 46 and Thr 119 , thereby enhancing the association of 3f with the core eIF3 subunits during apoptosis and inhibiting protein synthesis [120]. Interestingly, 3f was found to promote rRNA degradation through its direct interaction with and sequestration of heterogeneous nuclear ribonucleoprotein (hnRNP) K, an essential RNA binding and stabilizing protein [40]. Related to its rRNA regulation, 3f also blocks the 3′ end processing of HIV-1 pre-mRNA through 9G8 and CDK11, thereby inhibiting HIV replication [121].…”

Expression of Eukaryotic Initiation Factor 3f Is Associated with Prognosis in Gastric Carcinomas

“…Although the role of eIF3f in the eIF3 complex has not been defined [11,12,13], shut-off experiments in Schizosaccharomyces pombe showed that over the long term, eIF3f is essential for viability [14]. Studies of translation inhibition indicate that, in mammalian cells, eIF3f is a negative regulator that plays an important role in human cancer [11,15]. We have shown that eIF3f expression is significantly decreased in many human cancers [10,15,16,17].…”