Abstract
The basic understanding of the biological effects of eukaryotic translation initiation factors (EIFs) remains incomplete, notably for their roles independent of protein translation. Different EIFs exhibit nuclear localization and DNA-related functions have been proposed, but the understanding of EIFs novel functions beyond protein translation lacks of integrative analyses between the genomic and the proteomic levels. Here, the noncanonical function of EIF3F was studied in human lung adenocarcinoma by combining methods that revealed both the protein–protein and the protein–DNA interactions of this factor. We discovered that EIF3F promotes cell metastasis in vivo. The underpinning molecular mechanisms involved the regulation of a cluster of 34 metastasis-promoting genes including Snail2, as revealed by proteomics combined with immuno-affinity purification of EIF3F and ChIP-seq/Q-PCR analyses. The interaction between EIF3F and signal transducer and activator of transcription 3 (STAT3) controlled the EIF3F-mediated increase in Snail2 expression and cellular invasion, which were specifically abrogated using the STAT3 inhibitor Nifuroxazide or knockdown approaches. Furthermore, EIF3F overexpression reprogrammed energy metabolism through the activation of AMP-activated protein kinase and the stimulation of oxidative phosphorylation. Our findings demonstrate the role of EIF3F in the molecular control of cell migration, invasion, bioenergetics, and metastasis. The discovery of a role for EIF3F–STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma could lead to the development of diagnosis and therapeutic strategies.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Bordeaux, France 4 Functional Genomics Center (CGFB), Proteomics Facility, 146Rue Léo Saignat, 33076 Bordeaux, France 5 Bordeaux-INP, Avenue des Facultés, 33405 Talence Cedex, France 6 CELLOMET, Functional Genomics Center (CGFB), 146 rue LéoSaignat, 33000 Bordeaux, FranceThe molecular mechanisms of tumorigenesis are classified as hallmarks as diverse as resistance to cell death, activation of invasion, and metastasis or deregulation of cellular energetics [1]
A major observation was that EIF3F associates with nuclear proteins including signal transducer and activator of transcription 3 (STAT3), a transcription factor that has been previously defined as a master regulator of cell migration and metastasis and that has been considered as a priority target for the development of anti-cancer therapeutic strategies [14]
The molecular mechanisms linking EIF3F overexpression and metastasis include (i) proteome remodeling with specific upregulation of the machinery involved in cell migration, invasion, and energy metabolism and (ii) nuclear activities including the partnering with STAT3 transcription factor and the regulation of a cluster of 34 genes involved in cell migration, invasion, and energy metabolism
Summary
France 4 Functional Genomics Center (CGFB), Proteomics Facility, 146. Rue Léo Saignat, 33076 Bordeaux, France 5 Bordeaux-INP, Avenue des Facultés, 33405 Talence Cedex, France 6 CELLOMET, Functional Genomics Center (CGFB), 146 rue Léo. The molecular mechanisms of tumorigenesis are classified as hallmarks as diverse as resistance to cell death, activation of invasion, and metastasis or deregulation of cellular energetics [1]. Acquisition of these malignant properties requires numerous alterations in cell signaling at the level of gene transcription, protein translation and posttranslational modifications, as coordinated by various oncogenes, tumor suppressors, transcription factors, and the tumor microenvironment. Different biological effects were reported following the ectopic overexpression of specific EIFs in the spontaneously immortalized murine NIH3T3 cell line, ranging from the stimulation of cell proliferation, as observed for EIF4E, EIF4B, or EIF5A2, Nuclear control of lung cancer cells migration, invasion and bioenergetics by eukaryotic translation
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