Oncogenic activation of EEF1A2 expression: a journey from a putative to an established oncogene.

Ectopic EEF1A2 expression enhanced the proliferative capacity of the SK-OV-3 ovarian carcinoma cell line [ 17 ]. Immortalized ovarian surface epithelial (IOSE) lines constitutively overexpressing EEF1A2 exhibited enhanced proliferation potential over more extended periods than parental cell lines or controls. Interestingly, EEF1A2 expressing lines proliferated better than their respective controls in low-serum conditions and even in the absence of serum [ 51 ]. In another study with mouse plasmacytomas, i.e., tumors of mature plasma cells, EEF1A2 knockdown expression decreased IL-6-mediated activation of STAT3 and AKT pathways, leading to a decrease in proliferation of plasmacytomas (PCT) cell lines with delayed cell-cycle entry [ 6 ]. In a study conducted to explore the pro-tumorigenic role of EEF1A2 in prostate cancer, siRNA-mediated suppression of eEF1A2 protein resulted in reduced proliferation rate and colony formation in two prostate cancer cell lines, DU-145 and PC-3 [ 36 ]. Suppression of EEF1A2 led to substantial upregulation of proteins associated with the apoptosis pathway, namely caspase-3, BAD, BAX, and PUMA. EEF1A2 overexpression increases cell proliferation in the SW1990 pancreatic cancer cell line [ 42 ]. Overall, the research consistently demonstrates that EEF1A2 expression promotes enhanced cell proliferation across various cancer types, suggesting its potential as a protumorigenic factor with implications for therapeutic targeting. Escaping apoptosis is a major mechanism via which tumor cells remain viable and proliferate. Initial clues hinting at the anti-apoptotic role of eEF1A2 came from studies in myotubes, where EEF1A2 was found to exert a pro-survival effect, in stark contrast to EEF1A1, which exerted a pro-death activity [ 52 ]. Further evidence emerged upon discovering that EEF1A2 binds to Prdx-I, making the cells resistant to oxidative stress-induced cell death as a result. EEF1A2 was subsequently found to support tumor cell survival via abrogation of apoptosis in HCC [ 53 ], mouse plasmacytomas [ 6 ], and prostate cancer [ 36 ]. Dependence on EEF1A2 for resistance to apoptosis has also been documented in PA-1 ovarian cancer cells [ 51 ] and SH-SY5Y neuroblastoma cells [ 54 ]. These research findings strongly indicate that EEF1A2 plays a crucial role in promoting tumor cell survival by preventing apoptosis, as evidenced in multiple cancer types, and its binding to Prdx-I contributes to resistance against oxidative stress-induced cell death. Over the past decade, a substantial body of evidence has been amassed, strongly indicating that EEF1A2 plays a crucial role in promoting the migratory and invasive characteristics of tumor cells. Amiri et al. [ 55 ] showed that ectopic expression of EEF1A2 enhanced cell migration and invasion in the TNBC line BT54 via activation of the PI3K–AKT signaling cascade in cytoskeletal remodeling. Likewise, the PI3K/AKT/NF-kB cascade was responsible for mediating an eEF1A2-associated increase in migratory and invasive properties of HCC cell lines [ 53 ]. siRNA-based knockdown of EEF1A2 resulted in a reduction in migratory abilities of metastatic prostate cancer cell line PC3. EEF1A2 imparted a more intense pro-migratory property to TNBC cell line MDA-MB-231 than MCF7 in an ERK-dependent manner [ 56 ]. EEF1A2 could increase migration and invasion in neuroblastoma and glioblastoma cell lines in a PI3K-dependent manner [ 57 ]. Collectively, the evidence presented strongly supports the conclusion that EEF1A2 plays a crucial role in promoting migratory and invasive characteristics of tumor cells through various signaling cascades, suggesting it as a potential target for therapeutic interventions in multiple cancer types. Panasyuk et al. [ 58 ] came up with an interesting hypothesis to explain the differential abilities of EEF1A isoforms in nontranslational functions. They showed that EEF1A2, but not EEF1A1, was able to interact with SH2 and SH3 domains of various signaling molecules. Hence, it could act as a more potent mediator of phosphotyrosine-mediated signaling. The ability of EEF1A2 to bind phosphatidylinositol-4 kinase β, leading to an increase in its lipid kinase activity and subsequent increase in phosphatidylinositol-4 phosphate production, weighs in on this role of EEF1A2 [ 9 ]. The exclusive ability of EEF1A2 to interact with other proteins became more evident when it was shown that TSPY , an oncogene, binds more strongly with EEF1A2 than EEF1A1. EEF1A2 has also been reported to enhance cell survival and proliferation via interaction with PRDX1, PKR, and SNX16 [ 59 – 61 ]. A recent study in LUAD showed that EEF1A2 interacts with HSP90AB1 and enhances TGFβ receptor leading to phosphorylation of SMAD3 expression and nuclear localization promoting EMT [ 37 ]. While these reports highlight the role of EEF1A2 in mediating oncogenic roles via interaction with protein partners, EEF1A2 itself has been reported to be affected by binding with other proteins. p16INK4a, a tumor suppressor protein belonging to the INK4 family of CDK inhibitors, was found to reduce the expression and function of EEF1A2 , imparting its antiproliferative effects in the process [ 11 ] (Fig.  6 ). Fig. 6 The oncogenic mechanisms of EEF1A2 . Interacting partners of EEF1A2 and signaling pathway which regulate tumorigenesis. Arrows represent regulation of pathways and phenotype of tumor regulated through EEF1A2 . T-shaped arrows indicate inhibition of targeted pathway The oncogenic mechanisms of EEF1A2 . Interacting partners of EEF1A2 and signaling pathway which regulate tumorigenesis. Arrows represent regulation of pathways and phenotype of tumor regulated through EEF1A2 . T-shaped arrows indicate inhibition of targeted pathway The research by Panasyuk et al. and subsequent studies underscore the significant role of EEF1A2 in mediating cell survival and oncogenic processes through its distinct protein interactions, shedding light on its potential as a key player in various cellular pathways and highlighting its intricate interplay with other proteins [ 58 ]. Studies have frequently highlighted the role of the PI3K–AKT axis in mediating EEF1A2-mediated oncogenic effects in cells. Evidence of this effect came initially from the study of Amiri et al. [ 55 ] in breast cancer, which showed that EEF1A2 activated AKT and AKT-dependent actin remodeling for fueling migratory and invasive properties of the cells. The oncogenic effects of EEF1A2 in mice PCT were exerted via activation of JAK/STAT and AKT signaling [ 6 ]. EEF1A2 was found to enhance tumorigenic properties of HCC cell lines by stabilizing the oncogenic MDM4 protein via inactivation of p53 in a PI3K/AKT/mTOR-dependent manner [ 12 ]. EEF1A2 knockdown in HCC cell lines in yet another study led to the abrogation of cancerous attributes of the tumor cells via the reduction of PI3K/AKT/NF-kB signaling [ 53 ]. SNX16 interaction with EEF1A2 triggers a c-Myc signaling cascade [ 61 ]. Our investigations have further elucidated the significant role of EEF1A2 expression levels in neuroblastoma and glioblastoma cell lines. These levels exhibit a direct correlation with the cells proliferative, migratory, and invasive capacities, operating within the confines of a PI3K–AKT-dependent pathway [ 57 ]. Our team delved into the behavior of the triple-negative breast cancer cell line MDA-MB-231. Through the introduction of ectopic EEF1A2 expression, we observed a substantial augmentation in metastatic attributes. This effect was attributed to the activation of the ERK pathway [ 56 ]. Overall, EEF1A2 plays a crucial role in mediating oncogenic effects in various cancer types, operating through the activation of multiple signaling pathways, including PI3K–AKT, JAK/STAT, and ERK, which promote tumor cell migration, invasion, and proliferation (Fig.  6 ).

In 1993, EF-1α2 (or EEF1A2 as it came to be known later) protein was initially identified as a novel variant of EF-1α (or EEF1A1) protein and found to share 75% similarity in the coding regions at the nucleotide level and 96% similarity in the amino-acid sequence with the latter. The expression pattern of EEF1A2 was found to be quite different from EEF1A1 (Fig.  2 A). Northern blotting analysis revealed that it was highly expressed exclusively in skeletal muscle, heart muscle, and brain; which are essentially tissues where most cells are fully differentiated with very little or no cell division. EEF1A1, on the other hand, was expressed ubiquitously in the rest of the tissues, with significantly high rates of cell proliferation in liver, lung, and placenta [ 27 ]. Another study undertaken in rats showed that reduction in EF-1α mRNA levels during brain, heart, and muscle development occurs concomitantly with activation of S1 (the rat version of EF-1α2) gene expression. It was followed by a terminal differentiation process in the brain, heart, and muscle [ 28 ], indicating a developmental regulation of the expression of both isoforms in a tissue-specific manner. The grave consequences of the disruption of this isoform switching became evident when it was identified that the mutation responsible for autosomal recessive wasted (wst) phenotype in mice was essentially a 15.8 kb deletion spanning the promoter region and first noncoding exon of EEF1A2 gene. These mice exhibit typical features associated with muscle wasting and neurological and immunological abnormalities commencing at 21 days, and eventually leading to the death of the mice at 28 days. Interestingly, this timeline of manifestation of wasted mice symptoms falls in near-perfect synchrony when EEF1A2 expression takes over from EEF1A1 in specialized tissues of the heart, brain, and muscle [ 29 ]. The exact timing, location, and evolutionary importance of this switch were further explored in subsequent studies in mice [ 30 ] and Xenopus [ 31 ]. On postnatal day 2, the expression of EEF1A2 cannot be detected in skeletal muscle. However, there is observable expression of EEF1A1 in both skeletal and heart muscle tissues. At day 8, both EEF1A1/2 are expressed in heart and skeletal muscle. However, by day 15 EEF1A1 is slightly detectable in muscles. At day 21, EEF1A1 expression is not detectable in skeletal muscle continuing to complete depletion of expression till day 25 from heart too, and EEF1A2 expression takes over the function of EEF1A1 in mice [ 29 ] and rats [ 28 ] (Fig.  2 B). Another report in Xenopus , reported that EEF1A2 is also conserved in nonmammalian vertebrate species. Also, EEF1A1 protein is undetectable by adulthood which is posttranscriptionally controlled and EEF1A1 mRNA remains similar to EEF1A2 [ 31 ]. Fig. 2 Overview of organ specific switching of EEF1A1 to EEF1A2 . A EEF1A1 is expressed in all organs (liver, kidney, lungs, alveolar type1 and type 2 cells) to carry out its canonical functions, except heart, skeletal muscle, and brain where EEF1A2 expression carries out canonical function. B Mice symbol (alive or dead) in weighing dish with cerulean and aegean color represent the specific organs for EEF1A1 and EEF1A2 expression. Boxes with yellow or green colors represent EEF1A1 and EEF1A2 expression inside specific organs. Red cross sign represents no expression in organs Overview of organ specific switching of EEF1A1 to EEF1A2 . A EEF1A1 is expressed in all organs (liver, kidney, lungs, alveolar type1 and type 2 cells) to carry out its canonical functions, except heart, skeletal muscle, and brain where EEF1A2 expression carries out canonical function. B Mice symbol (alive or dead) in weighing dish with cerulean and aegean color represent the specific organs for EEF1A1 and EEF1A2 expression. Boxes with yellow or green colors represent EEF1A1 and EEF1A2 expression inside specific organs. Red cross sign represents no expression in organs

As aberrant overexpression of EEF1A2 is an exclusive nature of cancerous cells, it presents itself as an attractive candidate for therapeutic intervention in cancers. The canonical function carried out by EEF1A2 in cells is redundant with the activities of the other EEF1A isoform, EEF1A1 , which is also a promising candidate for targeting cancers. This is because EEF1A1 is an abundant cellular protein already present more than its partners in protein synthesis (molar ratios for EEF1A:EEF1B and EEF1A: ribosomes of 10:1 and 25:1, respectively) [ 62 ]. Thus, a 70% knockdown of EEF1A1 itself will not have any deleterious effect on the regular translational activity of cells under nonstress conditions. Nonetheless, EEF1A2 does not present such a situation. In recent years, multiple reports have emerged that have investigated the efficacy of selective targeting of EEF1A2 in cancerous cells, and the results are pretty encouraging. Several reports utilizing shRNA or siRNA-based targeting of EEF1A2 levels in cancerous cell lines have shown how depletion of EEF1A2 compromises the oncogenic potential of tumor cells [ 53 ]. Interestingly, EEF1A2 has been found to be a target of miR-663 and miR-744, which inhibit resveratrol-induced growth of MCF7 cells [ 20 ]. Most importantly, a marine natural product, plitidepsin, exerted its antitumor activity by targeting EEF1A2. What is more encouraging is that as of 2016, this drug has already successfully been in phase III clinical trials for multiple myeloma [ 22 ]. In a cancer-specific manner, EEF1A2 has been reported to promote specific pathways, for example, TGF-β/SMAD signaling in lung adenocarcinoma [ 37 ], the PI3K/AKT/mTOR pathway in hepatocellular carcinoma [ 12 ], the ERK pathway in breast cancer [ 56 ], and PI3K signaling in brain cancer [ 57 ]. Targeting EEF1A2 with plitidepsin and cancer-specific pathway inhibitors [check https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/approved-drug-list for US Food and Drug Administration (FDA)-approved targeted therapy drugs] may provide a synergistic effect to inhibit cell survival and proliferation. Specific gene therapy targeting EEF1A2 using clustered regularly interspaced short palindromic repeats (CRISPR) or an anti- EEF1A2 peptide can be designed to target EEF1A2 interactions, which can hinder the tumorigenesis property of cancer. In conclusion, targeting EEF1A2 holds significant promise as a therapeutic strategy for cancer treatment. The progress in understanding the specific mechanisms and pathways associated with EEF1A2 in different cancer types, coupled with the availability of targeted therapies such as plitidepsin, provides hope for more effective and precise cancer treatments in the future. Further research and clinical studies are warranted to explore the full potential of eEF1A2 as a target for cancer therapy, and to develop innovative and personalized treatments to combat this devastating disease.

Using combined fluorescence in situ hybridization (FISH) and PCR analysis, EEF1A2 and EEF1A1 were assigned chromosomal positions 20q13.3 and 6q14, respectively [ 23 ]. The human EEF1A2 gene extends nearly 10 kb and comprises eight exons and seven introns. The genomic structure of the EEF1A2 gene is identical to that of EEF1A1 , containing the same number of exons as EEF1A1 (Fig.  1 ). All positions of intron–exon boundaries are preserved inside the coding region [ 24 ]. However, despite the high degree of homology within the coding regions of the two genes, the EEF1A2 gene is almost thrice as large as EEF1A1 , owing to larger introns. In addition, there is dissimilarity between the 5′ untranslated region (UTR), 3′ UTR, and upstream promoter elements of the two genes. The predominant transcription start site for EEF1A2 is located at an adenine residue, 166 bp upstream of the initial AUG codon and resembles the consensus sequence of an Inr element, which possesses a consensus sequence 5′-YYA +1 N(A/T)YY-3′, where A +1 corresponds to the first transcribed base. Nucleotides A +1 , (A/T) +3 , and Py −1 play a critical role in Inr-mediated transcriptional initiation activity, as emphasized by Smale in 1997. Notably, these particular bases are conserved in the putative initiator of EEF1A2 [ 24 , 25 ]. On the other hand, the major transcription start site for the EEF1A1 gene has been mapped to a cytosine residue present within a stretch of consecutive pyrimidines, a typical feature of ribosomal protein genes. Further analysis reveals that while EEF1A1 contains a TATA box upstream of the transcription initiation site, EEF1A2 lacks it [ 26 ]. GC analysis of EEF1A2 gene revealed that the first exon is present within a CpG island. Promoter analysis of the EEF1A2 gene revealed consensus sequences for important cis -regulatory elements, such as an E-box (a crucial regulatory element for muscle-specific genes) and an EGR binding site [ 24 ]. Fig. 1 Promoter comparison of both EEF1A isoform. A Promoter of EEF1A2 reveals a presence of EGR binding site and E-box. CpG island is present of Exon1. Predominant transcription start site (TSS) is present at −166 position from initiator codon. Core promoter region spans from −16 to + 92 bp. B EEF1A1 promoter discloses a presence of TATA box at −24 position Promoter comparison of both EEF1A isoform. A Promoter of EEF1A2 reveals a presence of EGR binding site and E-box. CpG island is present of Exon1. Predominant transcription start site (TSS) is present at −166 position from initiator codon. Core promoter region spans from −16 to + 92 bp. B EEF1A1 promoter discloses a presence of TATA box at −24 position

EEF1A proteins are not only involved in translation elongation process, but also in multiple noncanonical functions. The upregulation of EEF1A2 in various cancers such as ovarian, hepatocellular, breast, prostate, lung, and pancreatic, signifies its role in tumorigenesis. So far, the research has fully established the role of EEF1A2 as an oncogene and in the regulation of JAK/STAT, ERK, PI3K/AKT/NF-kB, or mTOR oncogenic pathways. Numerous studies have highlighted the correlation between EEF1A2 and cancer prognosis, suggesting its potential as a biomarker. Nonetheless, additional research is necessary to determine its accuracy and reliability as a biomarker within clinical settings. It is imperative to conduct further validations in larger and more diverse cohorts to firmly establish its potential utility. Furthermore, the specific upregulation of EEF1A2 in cancers renders it an appealing target for drug development.

The role of translation factors in cancers attracted the attention of researchers upon the discovery of the role of members of the proteins of the eukaryotic translational initiation machinery in different cancers. Among the elongation factors, members of the EEF1A protein family have garnered the most attention. Both EEF1A1 and EEF1A2 have been reported to be involved in mediating oncogenic processes, while the former has been associated with both pro- and anticancerous roles, EEF1A2 has established itself as a potent oncogene in recent times. Table 1 presents compelling evidence for the role of EEF1A2 as an oncogene across various cancer types. The majority of studies feature robust sample sizes of over 50 patients, with only two exceptions in the case of prostate cancer and one in ovarian cancer. Table 1 EEF1A2 expression in cancer tissue and normal tissue, and its biological significance Cancer type EEF1A2 expression Biological significance References Cancer tissue (No. of samples) Normal tissue (No. of samples) Ovarian cancer High (159/500) NA No change in prognosis [ 17 ] None, low, moderate (341/500) Serous tumors with high EEF1A2 expression show good prognosis Ovarian cancer High (3/148) NA NA [ 32 ] Moderate (7/148) Low (49/148) None (89/148) Ovarian cancer High (10/10) compared with benign endometriosis NA NA [ 33 ] Breast cancer High (79/380) NA Good prognosis [ 18 ] Moderate (177/380) Good prognosis Low (76/380) None (48/380) Breast cancer High (5/46) Low (7/7) NA [ 34 ] Moderate (22/46) Low (19/46) Triple-negative breast cancer High (3/84) NA Poor prognosis [ 35 ] Moderate (11/84) Low (48/84) None (22/84) compared with adjacent tissue Prostate cancer High (3/4) None (1/1) NA [ 14 ] None (1/4) Prostate cancer High compared with adjacent normal tissue (26/30) NA NA [ 36 ] Prostate cancer High (40/40) compared with benign tumor (8/8) NA Poor prognosis [ 19 ] Non-small cell lung cancer High (58/69) compared with adjacent normal tissue of 46 patients NA Good prognosis [ 38 ] Lung adenocarcinoma High compared with adjacent normal tissue (32/113) NA Poor prognosis [ 16 ] Lung adenocarcinoma High compared with adjacent normal tissue (78/78) NA Poor prognosis [ 37 ] Pancreatic cancer High (41/62) NA NA [ 7 ] Pancreatic ductal adenocarcinoma High (76/97) NA Poor prognosis [ 15 ] Pancreatic cancer High (29/35) No expression (8/8) NA [ 42 ] Chronic pancreatitis shows no expression (13/13) Hepatocellular carcinoma High (30/100) None or very weak (27/27) NA [ 45 ] Moderate (24/100) Adjacent normal tissue (84), high (1/84), moderate (14/84), weak (52/84), none (17/84) Weak (29/100) None (17/100) Hepatocellular carcinoma High (24/48) NA Poor prognosis [ 12 ] Low (24/48) NA Good prognosis Hepatocellular carcinoma High (47/62) None (20/20) NA [ 53 ] Paired pericarcinomatous High (5/62) Gastric cancer High (105/129) Weak (9/24) Poor prognosis [ 46 ] None (15/24) NA not available in the study EEF1A2 expression in cancer tissue and normal tissue, and its biological significance NA not available in the study Although further research is required to conclusively establish EEF1A2 as a biomarker, its potential is promising, as multiple studies have demonstrated its association with cancer prognosis. It has been identified as an independent prognostic indicator for extended survival in serous cancer [ 17 ]. Additionally, it has been reported as a positive prognostic marker for breast cancer cases without lymph node involvement, and conversely, a negative prognostic marker for triple-negative breast cancer [ 18 , 35 ]. In pancreatic cancer, its correlation with lymph node metastasis suggests its potential as an adverse prognostic marker [ 15 ]. In gastric cancer, the observed overexpression of EEF1A2 has been established as an independent indicator for predicting poor prognosis [ 46 ]. Furthermore, in stage I non-small cell lung cancer patients, EEF1A2 has been identified as a surrogate marker for poorer prognosis [ 16 , 38 ]. In the context of prostate cancer, the overexpression of EEF1A2 in metastatic prostate cancer suggests its potential as a tissue-based biomarker for monitoring cancer progression and cell transformation [ 19 ]. Additionally, in late-stage ovarian cancer, particularly in cases of serous endometrium cancer, the amplification of the 20q13 locus and EEF1A2 copy number further underscore its potential as a biomarker for assessing patient survivability [ 3 ]. Moreover, elevated levels of EEF1A2 in hepatocellular carcinoma biopsy samples suggest its potential as a diagnostic marker [ 12 ]. Collectively, these studies provide substantial evidence supporting the role of EEF1A2 in cancer prognosis. Given these strong indications, it is imperative to conduct large-scale and systematic studies to firmly establish EEF1A2 as a biomarker for various types of cancers. We have identified notable disparities in EEF1A2 expression across ovarian cancer, gastric cancer, and acute myeloid leukemia datasets derived from TCGA and individual reports. These discrepancies can be attributed to several factors. In the case of ovarian cancer, TCGA lacks information on normal tissue for comparison and does not distinguish between different subtypes, such as serous, endometrioid, mucinous, and clear cell. In contrast, scientific reports place emphasis on specific tissue types [ 17 , 32 ]. Regarding acute myeloid leukemia, the study was conducted on cell lines (AML-193, Kasumi-1, and KG-1), rather than patient-derived cancer tissue. This difference in sample source may contribute to the observed disparity. Another potential reason for the inconsistency is that TCGA data is primarily RNA based, whereas other reports are based on protein expression data. Protein levels provide a more reliable indicator of functional implications in tumorigenesis. Additionally, the RNA data of TCGA relies on high-throughput platforms, which necessitates validation through RT–PCR. To address these discrepancies, an analysis of EEF1A2 protein expression within the same TCGA dataset at the protein level could offer valuable insights and potentially resolve the observed differences. We have discussed the multiple facets of regulation mediated by EEF1A2 in cancer progression. Unlike EEF1A1, EEF1A2 is able to interact with a number of binding partners and mediate the activation of key oncogenic pathways. The widely reported misexpression and redundant role of eEF1A2 in protein translation make eEF1A2 a very promising candidate for targeted therapy in cancers. We have discussed the multiple approaches in which this could be achieved. In this regard, dual targeting of both EEF1A isoforms could also be considered, since targeting of EEF1A1 isoform has also shown promising results in certain cancers such as HCC. The decision to target one or both of the EEF1A isoforms should be taken after consideration of the role of degree of pro-oncogenic role played by them in the specific tissue type [ 35 ], since we also see that EEF1A2 could be associated with a better survival rate in certain cancers. Likewise, neoangiogenesis is essential for metastasis, and the role of EEF1A2 in the regulation of the formation of a blood vessel in tumors needs urgent attention. EEF1A2 targeting therapies could hold promise in a wide variety of cancer types. Plitidepsin-related clinical studies are still going on and are currently in the phase III stage for the treatment of lung and breast cancer, while it has successfully completed a phase III trial for multiple myeloma [ 22 , 63 ].

EEF1A1 and EEF1A2 are two isoforms of the EEF1A, which play essential roles in the elongation step of protein translation. EEF1A2 and EEF1A1 genes have been mapped to chromosomal positions 20q13.3 and 6q14, respectively. Despite their high degree of similarity in coding regions, they exhibit differences in genetic structure and expression patterns. EEF1A1 is mostly ubiquitously expressed; in contrast, EEF1A2 exhibits a more restricted expression pattern, primarily found in differentiated tissues such as skeletal muscle, heart muscle, adrenal gland, oral mucosa, esophagus, seminal vesicle, testis, pancreatic islets, and brain [ 1 , 2 ]. EEF1A2 was initially identified as a highly overexpressed gene in 30% of ovarian tumors by Anand et al. [ 3 ]. Subsequent studies identified EEF1A2 as a putative oncogene across various cancers, including breast, liver, gastric, pancreatic, and lung cancers [ 4 ]. EEF1A was reported as a housekeeping gene, and the findings that housekeeping genes were upregulated, activated, or mutated in carcinomas were dismissed because they do not align with kinase-driven oncogenesis [ 5 ]. Further detailed in vitro and in vivo studies established the role of EEF1A2 in imparting oncogenic properties to cells and modulating JAK/STAT, PIP4, AKT, and PI3K/AKT/mTOR signaling pathways [ 6 – 14 ]. EEF1A2 overexpression has generally been associated with poorer prognosis in pancreatic ductal adenocarcinoma, non-small cell lung carcinoma, and ovarian cancer patients [ 15 – 17 ]. However, in breast cancer, it has been associated with better survival [ 18 ]. In addition, EEF1A2 has been demonstrated to serve as an autonomous biomarker for the purpose of risk stratification in the context of prostate cancer [ 19 ]. Ever since the multiple roles and widespread overexpression of EEF1A2 in carcinomas have been identified, efforts have been made to target it for anticancer therapy utilizing miRNAs, natural products, and drugs [ 20 – 22 ]. In this review, we aim to summarize the research findings from 1991 to 2023 on the role of EEF1A2 as an oncogene across a wide variety of cancers. We will discuss the pathways that are perturbed by abnormal EEF1A2 levels and the role of EEF1A2 in driving the tumorigenesis process. To understand the effect of EEF1A2 on survival, we will be discussing the correlation of EEF1A2 levels with the survival rates of patients in different carcinomas. Lastly, we aim to shed some light on the prospects of EEF1A2 as a candidate drug target and summarize the findings to date in this regard.