Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1): A Target for Cancer Therapeutic Intervention
Jaiswal P, Koul S, Palanisamy N, and Koul HK. Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1): A Target for Cancer Therapeutic Intervention. Cancer Res 2019; 79(13).
Introduction: Cap-dependent mRNA translation is an essential for translation of key oncogenic proteins at optimal levels and is highly regulated by the rate limiting, initiation step in protein synthesis, thus this pathway could be exploited for therapeutic intervention in oncogene driven tumors. Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) serves as the critical 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 cancers panels through various approaches. Methods: Immunohistochemistry analysis of EIF4G1 protein was done on multi-organ Human Cancer tissue microarray (TMA) derived from patient's samples from different cancers. Western blots for EIF4G1 protein was done for different cell lines in representing the different cancer type. Multiple clinical cohorts were used to analyze the EIF4G1 mRNA expression across human cancers. TCGA data analysis of EIF4G1 was done through Ualcan and c-bioportal web servers. Dependency score was calculated through Cancer Dependency Map. Results: We analyzed the EIF4G1 protein level by western blot in variety of human cancer cell lines found an elevated level of EIF4G1 protein in these cell lines. We found an increase in EIF4G1 protein levels in tissue sections from different cancer samples as compared to their respective normal tissue. EIF4G1 expression was also elevated across cancer cell lines from multiple organs. Our analysis of the TCGA data revealed the higher expression of EIF4G1 mRNA expression across human cancers. Comparison of EIF4G1 mRNA expression between tumor tissue vs normal tissue in TCGA datasets revealed higher expression of EIF4G1 in cancer tissues. We discovered that alteration frequency in EIF4G1 is prevailed across different human cancers in particular prostate cancer (∼25%), ovarian cancer (∼15%), Head & neck cancer (∼13%) and cervical cancer (∼12.5%) were most affected cancer. EIF4G1 Amplification and mRNA upregulation was evident across human cancer. We further analyzed the dependency of EIF4G1 in cancer cell survival based on depletion assay through DepMap and found that EIF4G1 is required for cancer cell survival. Higher EIF4G1 mRNA level was associated with lower survival of patients in Pan Cancer analysis. Conclusions: This is the first study highlighting a broad role for EIF4G1 across pan cancers suggesting that EIF4G1 may serve as a novel target for therapy in multiple malignancies. However further studies are required to develop these concepts and test usefulness of targeting EIF4G1 in caner utilizing preclinical model systems.