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.

Highlights

  • Deregulated translation plays an important role in human cancer [1]

  • We demonstrated that eukaryotic initiation factor 3 subunit f (eIF3f) expression significantly decreased in many human cancers [6,9,10]

  • Using quantum dot (Qdot)-labeled eIF3f antibody, we demonstrated that eIF3f was markedly decreased in pancreatic adenocarcinoma tissue, as compared with normal pancreatic ducts (Fig. S1A)

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Summary

Introduction

Deregulated translation plays an important role in human cancer [1]. The translation process can be divided into 4 phases: initiation, elongation, termination, and ribosome recycling [2]. We showed that restored eIF3f expression in tumor cells causes ribosomal RNA (rRNA) degradation, inhibits translation and cell proliferation, and induces apoptosis [6]. We tested the hypothesis that eIF3f coordinates with hnRNP K to regulate rRNA degradation and that decreased eIF3f expression contributes to tumorigenesis by deregulating translation and apoptosis.

Results
Conclusion

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