Understanding and targeting the disease‐related RNA binding protein human antigen R (HuR)

Focus Article

Christopher W. Schultz, Ranjan Preet, Teena Dhir, Dan A. Dixon, Jonathan R. Brody

Published Online: Jan 23 2020

DOI: 10.1002/wrna.1581

Full article on Wiley Online Library: HTML PDF

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Abstract Altered gene expression is a characteristic feature of many disease states such as tumorigenesis, and in most cancers, it facilitates cancer cell survival and adaptation. Alterations in global gene expression are strongly impacted by post‐transcriptional gene regulation. The RNA binding protein (RBP) HuR (ELAVL1) is an established regulator of post‐transcriptional gene regulation and is overexpressed in most human cancers. In many cancerous settings, HuR is not only overexpressed, but it is “overactive” as denoted by increased subcellular localization within the cytoplasm. This dysregulation of HuR expression and cytoplasmic localization allows HuR to stabilize and increase the translation of various prosurvival messenger RNA (mRNAs) involved in the pathogenesis of numerous cancers and various diseases. Based on almost 20 years of work, HuR is now recognized as a therapeutic target. Herein, we will review the role HuR plays in the pathophysiology of different diseases and ongoing therapeutic strategies to target HuR. We will focus on three ongoing‐targeted strategies: (1) inhibiting HuR's translocation from the nucleus to the cytoplasm; (2) inhibiting the ability of HuR to bind target RNA; and (3) silencing HuR expression levels. In an oncologic setting, HuR has been demonstrated to be critical for a cancer cell's ability to survive a variety of cancer relevant stressors (including drugs and elements of the tumor microenvironment) and targeting this protein has been shown to sensitize cancer cells further to insult. We strongly believe that targeting HuR could be a powerful therapeutic target to treat different diseases, particularly cancer, in the near future. This article is categorized under: RNA in Disease and Development > RNA in Disease NRA Turnover and Surveillance > Regulation of RNA Stability Translation > Translation Regulation

Timeline of human antigen R (HuR) discoveries, and discoveries specifically targeting HuR's role in cancer. HuR was first cloned in 1996, however, it has only been in the last decade that HuR has been more widely accepted as an important target in cancer. This chart details the total number of publications focused on HuR, and relevant discoveries relating to targeting HuR in cancer

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Methods of targeting human antigen R (HuR). HuR is commonly targeted in one of three ways. (1) Targeting HuR's expression levels, (2) translocation, and (3) target mRNA binding. There are various potential therapeutics that target HuR at each one of these three steps. Overall, the inhibition of HuR leads to an inhibition of the tumorigenic pathways that HuR promotes

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Human antigen R (HuR) as a sensitizer. HuR inhibition has been used as a successful means to sensitize cancer calls. Standard of care chemotherapeutics causes damage which activates HuR causing a rapid response and stabilization of prosurvival mRNA. This leads to cell survival and chemotherapeutics resistance. Inhibition of HuR in response to DNA damaging agents can be accomplished through either inhibition of HuR expression (here shown with siRNA carrying nanoparticles), HuR translocation (here shown with pyrvinium), or target binding (here shown with 15,16‐dihydrotanshinone I [DHTS]), all of which would in this case lead to the loss of regulation of targets such as proto‐oncogene serine/threonine‐protein kinase (PIM1) or cell division cycle 6 (CDC6) and enhanced cell sensitivity

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Structure and function of human antigen R (HuR). The crystal structure of RNA recognition motifs 1 and 2 (RRMs 1 and 2) bound to RNA has been determined, as has that of two RRM3 (as could potentially be observed with an HuR dimer) moieties bound to RNA. While the crystal structure of the hinge region and thus the HuR nucleocytoplasmic shuttling sequence (HNS) has not been determined, studies have confirmed the overall importance of post‐translational modifications in this region governing the localization of HuR between the cytoplasm and the nucleus

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