Elongation factor-2 kinase (eEF-2K) expression is associated with poor patient survival and promotes proliferation, invasion and tumor growth of lung cancer

Bircan, Hacı Ahmet; Gürbüz, Nilgün; Pataer, Apar; Caner, Ayşe; Kahraman, Nermin; Bayraktar, Emine; Bayraktar, Recep; Erdoğan, Mümin Alper; Kabil, Nashwa; Özpolat, Bülent

doi:10.1016/j.lungcan.2018.07.027

Cited by 40 publications

(39 citation statements)

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“…Taken together with the roles of eEF2K in promoting the survival of cancer cells under nutrientdeprived conditions [6,38,39], in cell migration and cancer cell metastasis [9], and in angiogenesis [10], our present data add further support to the conclusion that disabling eEF2K may be a valuable therapeutic approach to tackling established solid tumours, at least for some types of cancers. However, as is the case with targeting other processes such as autophagy and mTORC1 signaling [2,48,49], in some specific settings the inhibition of eEF2K may actually promote cancer-related processes, e.g., tumour initiation.…”

Section: Discussionsupporting

confidence: 79%

“…For example, we recently reported that depletion of eEF2K promotes growth of A549 xenografts in mice [37]. In direct contrast, eEF2K is also highly expressed in other cancers (see, e.g., [38,39] and is also activated under conditions (such as nutrient depletion or hypoxia [8]) which occur within solid tumours; this will permit the enhanced expression of PD-L1 increasing the resistance of the tumour cells to immune attack.…”

Section: Gene Expression Profiles Of Eef2k and Cd274 (Pd-l1) In A Datmentioning

confidence: 99%

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eEF2K enhances expression of PD-L1 by promoting the translation of its mRNA

Xie

Jin

et al. 2020

Biochemical Journal

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Emerging advances in cancer therapy have transformed the landscape towards cancer immunotherapy regimens. Recent discoveries have resulted in the development of clinical immune checkpoint inhibitors that are ‘game-changers’ for cancer immunotherapy. Here we show that eEF2K, an atypical protein kinase that negatively modulates the elongation stage of protein synthesis, promotes the synthesis of PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance. Ablation of eEF2K in prostate and lung cancer cells markedly reduced the expression levels of the PD-L1 protein. We show that eEF2K promotes the association of PD-L1 mRNAs with translationally active polyribosomes and that translation of the PD-L1 mRNA is regulated by a uORF (upstream open reading-frame) within its 5’-UTR (5’-untranslated region) which starts with a non-canonical CUG as the initiation codon. This inhibitory effect is attenuated by eEF2K thereby allowing higher levels of translation of the PD-L1 coding region and enhanced expression of the PD-L1 protein. Moreover, eEF2K-depleted cancer cells are more vulnerable to immune attack by natural killer cells. Therefore, control of translation elongation can modulate the translation of this specific mRNA, one which contains an uORF that starts with CUG, and perhaps others that contain a similar feature. Taken together, our data reveal that eEF2K regulates PD-L1 expression at the level of the translation of its mRNA by virtue of a uORF in its 5’-region. This, and other roles of eEF2K in cancer cell biology (e.g., in cell survival and migration), may be exploited for the design of future therapeutic strategies.

show abstract

Section: Discussionsupporting

confidence: 79%

Section: Gene Expression Profiles Of Eef2k and Cd274 (Pd-l1) In A Datmentioning

confidence: 99%

eEF2K enhances expression of PD-L1 by promoting the translation of its mRNA

Xie

Jin

et al. 2020

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…Taken together with the roles of eEF2K in promoting the survival of cancer cells under nutrientdeprived conditions [6,35,36], in cell migration and cancer cell metastasis [9], and in angiogenesis [10], our present data add further support to the conclusion that disabling eEF2K may be a valuable therapeutic approach to tackling established solid tumours, at least for some types of cancers. However, as is the case with targeting other processes such as autophagy and mTORC1 signaling [2,45,46], in some specific settings the inhibition of eEF2K may actually promote cancer-related processes, e.g., tumour initiation.…”

Section: Discussionsupporting

confidence: 77%

“…For example, we recently reported that depletion of eEF2K promotes growth of A549 xenografts in mice [34]. In direct contrast, eEF2K is also highly expressed in other cancers (see, e.g., [35,36] and is also activated under conditions (such as nutrient depletion or hypoxia [8]) which occur within solid tumours; this will permit the enhanced expression of PD-L1 increasing the resistance of the tumour cells to immune attack.…”

Section: Gene Expression Profiles Of Eef2k and Cd274 (Pd-l1) In A Datmentioning

confidence: 99%

eEF2 kinase enhances the expression of PD-L1 by promoting the translation of its mRNA

Xie

Jin

et al. 2020

Preprint

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Emerging advances in cancer therapy have transformed the landscape from conventional therapies towards cancer immunotherapy regimens. Recent discoveries have resulted in the development of clinical immune checkpoint inhibitors that are ‘game-changers’ for cancer immunotherapy. Here we show that eEF2K, an atypical protein kinase that inhibits the elongation stage of protein synthesis, actually promotes the synthesis of PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance. Ablation of eEF2K in prostate and lung cancer cells markedly reduced the expression levels of the PD-L1 protein. We show that eEF2K promotes the association of PD-L1 mRNAs with translationally active polyribosomes and that translation of the PD-L1 mRNA is regulated by a uORF (upstream open reading-frame) within its 5’-UTR (5’-untranslated region) which starts with a non-canonical CUG codon. This inhibitory effect is attenuated by eEF2K thereby allowing higher levels of translation of the PD-L1 coding region and enhanced expression of the PD-L1 protein. Moreover, eEF2K-depleted cancer cells are more vulnerable to immune attack by natural killer cells. Therefore, control of translation elongation can modulate the translation of this specific mRNA, one which contains an uORF that starts with CUG, and perhaps others that contain a similar feature. Taken together, our data reveal that eEF2K regulates PD-L1 expression at the level of the translation of its mRNA by virtue of a uORF in its 5’-region. This, and other roles of eEF2K in cancer cell biology (e.g., in cell survival and migration), may be exploited for the design of future therapeutic strategies.

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“…Protein-coding genes (PCGs) are thought to be involved in many important pathways and biological processes during tumourigenesis ( Ge et al, 2018 ; Liu et al, 2017 ; Zhang et al, 2017 ). A recent study found that Eukaryotic Elongation Factor-2 kinase ( eEF-2K ) expression was related to shorter overall survival in lung cancer patient ( Bircan et al, 2018 ). A 24-gene hypoxia signature represented independent prognostic and predictive value for patients with muscle invasive bladder cancer ( Yang et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

An RNA-sequencing-based transcriptome for a significantly prognostic novel driver signature identification in bladder urothelial carcinoma

Liu

Zhou

Liu

2020

PeerJ

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Bladder cancer (BC) is the ninth most common malignancy worldwide. Bladder urothelial carcinoma (BLCA) constitutes more than 90% of bladder cancer (BC). The five-year survival rate is 5–70%, and patients with BLCA have a poor clinical outcome. The identification of novel clinical molecular markers in BLCA is still urgent to allow for predicting clinical outcomes. This study aimed to identify a novel signature integrating the three-dimension transcriptome of protein coding genes, long non-coding RNAs, microRNAs that is related to the overall survival of patients with BLCA, contributing to earlier prediction and effective treatment selection, as well as to the verification of the established model in the subtypes identified. Gene expression profiling and the clinical information of 400 patients diagnosed with BLCA were retrieved from The Cancer Genome Atlas (TCGA) database. A univariate Cox regression analysis, robust likelihood-based survival modelling analysis and random forests for survival regression and classification algorithms were used to identify the critical biomarkers. A multivariate Cox regression analysis was utilized to construct a risk score formula with a maximum area under the curve (AUC = 0.7669 in the training set). The significant signature could classify patients into high-risk and low-risk groups with significant differences in overall survival time. Similar results were confirmed in the test set (AUC = 0.645) and in the entire set (AUC = 0.710). The multivariate Cox regression analysis indicated that the five-RNA signature was an independent predictive factor for patients with BLCA. Non-negative matrix factorization and a similarity network fusion algorithm were applied for identifying three molecular subtypes. The signature could separate patients in every subtype into high- and low- groups with a distinct difference. Gene set variation analysis of protein-coding genes associated with the five prognostic RNAs demonstrated that the co-expressed protein-coding genes were involved in the pathways and biological process of tumourigenesis. The five-RNA signature could serve as to some degree a reliable independent signature for predicting outcome in patients with BLCA.

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Elongation factor-2 kinase (eEF-2K) expression is associated with poor patient survival and promotes proliferation, invasion and tumor growth of lung cancer

Cited by 40 publications

References 51 publications

eEF2K enhances expression of PD-L1 by promoting the translation of its mRNA

eEF2K enhances expression of PD-L1 by promoting the translation of its mRNA

eEF2 kinase enhances the expression of PD-L1 by promoting the translation of its mRNA

An RNA-sequencing-based transcriptome for a significantly prognostic novel driver signature identification in bladder urothelial carcinoma

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