eEF2K enhances expression of PD-L1 by promoting the translation of its mRNA.
Yu Wu,Jianling Xie,Xin Jin,Roman V. Lenchine,Xuemin Wang,Danielle M. Fang,Zeyad D. Nassar,Lisa M. Butler,Jing Li,Christopher G. Proud +9 more
TLDR
The 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 which starts with a non-canonical CUG as the initiation codon.Abstract:
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.read more
Citations
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Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics
TL;DR: The authors review the transcriptional, post- transcriptional and translational regulation of PD-L1 expression in cancers as well as the diverse post-translational modifications, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination, that affect PD- L1 stability and activity.
Journal ArticleDOI
What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables
Andrea Palicelli,Martina Bonacini,Stefania Croci,Cristina Magi-Galluzzi,Sofia Canete-Portillo,Alcides Chaux,Alessandra Bisagni,Eleonora Zanetti,Dario de Biase,Beatrice Melli,Francesca Sanguedolce,Moira Ragazzi,Maria Paola Bonasoni,Alessandra Soriano,Stefano Ascani,Maurizio Zizzo,Carolina Castro Ruiz,Antonio De Leo,Guido Giordano,Matteo Landriscina,Giuseppe Carrieri,Luigi Cormio,Daniel M. Berney,Daniel Abensur Athanazio,Jatin Gandhi,Alberto Cavazza,Giacomo Santandrea,Alessandro Tafuni,Magda Zanelli +28 more
TL;DR: In this paper, the authors performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables.
Journal ArticleDOI
What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment.
Andrea Palicelli,Stefania Croci,Alessandra Bisagni,Eleonora Zanetti,Dario de Biase,Beatrice Melli,Francesca Sanguedolce,Moira Ragazzi,Magda Zanelli,Alcides Chaux,Sofia Canete-Portillo,Maria Paola Bonasoni,Alessandra Soriano,Stefano Ascani,Maurizio Zizzo,Carolina Castro Ruiz,Antonio De Leo,Guido Giordano,Matteo Landriscina,Giuseppe Carrieri,Luigi Cormio,Daniel M. Berney,Jatin Gandhi,Valerio Copelli,Giuditta Bernardelli,Giacomo Santandrea,Martina Bonacini +26 more
TL;DR: In this article, the authors performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs.
Journal ArticleDOI
MRTF-A-NF-κB/p65 axis-mediated PDL1 transcription and expression contributes to immune evasion of non-small-cell lung cancer via TGF-β.
Fu Du,Xin Qi,Aotong Zhang,Fanfan Sui,Xuemin Wang,Christopher G. Proud,Cunzhi Lin,Xinglong Fan,Jing Li +8 more
TL;DR: In this article, TGF-β upregulated the expression of the transcriptional coactivator MRTF-A in non-small-cell lung cancer cells, which subsequently interacted with NF-κB/p65 rather than SRF to facilitate the binding of NF-α to the PDL1 promoter, thereby activating the transcription and expression of PD-L1.
Journal ArticleDOI
Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase.
Darby J Ballard,Hao-Yun Peng,Jugal Kishore Das,Anil Kumar,Liqing Wang,Yijie Ren,Xiaofang Xiong,Xingcong Ren,Jin-Ming Yang,Jianxun Song +9 more
TL;DR: Eukaryotic Elongation Factor-2 Kinase (eEF2K) acts as a negative regulator of protein synthesis, translation, and cell growth, as a structurally unique member of the alpha-kinase family as mentioned in this paper.
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