Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1): a target for cancer therapeutic intervention?

Abstract

Background Cap-dependent mRNA translation is essential for the translation of key oncogenic proteins at optimal levels and is highly regulated by the rate limiting, initiation step in protein synthesis. Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) serves as a scaffold for assembly of cap-dependent translation components in EIF4F complex formation. In the current study, we analyzed the role and expression of EIF4G1 in Pan human cancer panels through various approaches. Methods Immunohistochemistry analysis of EIF4G1 protein was done on high-density multi-organ Human Cancer tissue microarray (TMA) derived from the patient samples from different cancers. We used multiple clinical cohorts to analyze the EIF4G1 mRNA expression across human cancers. TCGA data analysis of EIF4G1 was done through Ualcan and c-bioportal web servers. Western blots for EIF4G1 protein was done for different cell lines in representing the multiple cancer types. Dependency score was calculated through Cancer Dependency Map. Clonogenic, tumorosphere assay and cell invasion assay were done with EIF4G complex inhibitor. Association of EIF4G1 mRNA and Kaplan–Meier survival analysis was done on available TCGA datasets. Results We observed an increase in EIF4G1 protein levels in tissue sections from different cancers as compared to their respective normal tissue. Our analysis of the TCGA data revealed that EIF4G1 mRNA expression is significantly increased in tumor tissues compared to respective control tissues across human cancers and variable expression was observed among different datasets. We discovered that alteration frequency in EIF4G1 is prevalent in human cancers e.g. prostate cancer (~ 25%), ovarian cancer (~ 15%), Head and Neck cancer (~ 13%) and cervical cancer (~ 12.5%). EIF4G1 mRNA and protein levels were high across cancer cell lines from multiple organs. Our analysis of DepMap datasets utilizing depletion assays revealed that EIF4G1 is critical for cancer cell survival. Treatment with EIF4G complex inhibitor impaired clonogenic, tumorosphere formation potential and inhibited cell invasion. Moreover, higher EIF4G1 mRNA level was associated with a lower median survival of patients in multiple tumor types. Conclusions These studies show that EIF4G1 is amplified/over-expressed in multiple cancers and plays an essential role in cancer cell survival, as such EIF4G1 could serve as a novel potential target for therapeutic intervention across many cancers.

EIF4G1 and RAN as Possible Drivers for Malignant Pleural Mesothelioma

“…Thus, EIF4G1 acts as an oncoprotein [28] and represents an interesting CDG for further investigation as a possible therapeutic target for MPM. These findings corroborate recent work carried out by Jaiswal et al [29] on several types of cancers, including MPM. The authors showed that the overexpression of EIF4G1 was associated with a bad prognosis, leading them to conclude that EIF4G1 could be a novel potential target for therapeutic interventions [29].…”

“…These findings corroborate recent work carried out by Jaiswal et al [29] on several types of cancers, including MPM. The authors showed that the overexpression of EIF4G1 was associated with a bad prognosis, leading them to conclude that EIF4G1 could be a novel potential target for therapeutic interventions [29]. Based on mRNA expression data for EIF4G1 from TCGA datasets, they analyzed the survival of patients with different cancer, including mesothelioma.…”

Identification of miRNA signatures for kidney renal clear cell carcinoma using the tensor-decomposition method

“…3 (VI)] comes from a study of the effects of knockdown of the gene family of eukaryotic translation initiation factors (EIF) by RNAi in MCF10A cells. EIF3b is a promising prognostic biomarker and a potential therapeutic target for patients with clear cell renal cell carcinoma 32 , and EIF4GI is a target for cancer therapeutics 33 .…”

Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer

“…IHC analysis was performed using a rabbit polyclonal SYT13 antibody (OAAB02896; Aviva Systems Biology, San Diego, CA, USA) to analyze 40 sections from patients with pT4a gastric cancer, as previously described. 37 External validation cohorts were generated using global cohort data obtained from TCGA Research Network via the open source cBioPortal ( https://www.cbioportal.org/ ) 38 and the Kaplan-Meier Plotter ( http://kmplot.com/analysis/ ). 39 …”