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

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

RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

“…The human antigen R (HuR), the protein product of the ELAV1 gene, is a ubiquitously expressed RBP that contains three RNA recognition motifs (RRMs) via which it preferentially binds to adenylate/uridylate-rich RNA elements (AREs) [71][72][73]. AREs are signals for rapid RNA degradation, and by blocking these recognition sites HuR can stabilize its RNA interaction partners [71][72][73].…”

“…The human antigen R (HuR), the protein product of the ELAV1 gene, is a ubiquitously expressed RBP that contains three RNA recognition motifs (RRMs) via which it preferentially binds to adenylate/uridylate-rich RNA elements (AREs) [71][72][73]. AREs are signals for rapid RNA degradation, and by blocking these recognition sites HuR can stabilize its RNA interaction partners [71][72][73]. HuR is frequently upregulated in cancer cells and is known to be involved in many hallmarks of cancer, such as invasion, angiogenesis, and inflammation, by post-transcriptionally regulating various cancer-related mRNAs [71,72,[74][75][76].…”

“…AREs are signals for rapid RNA degradation, and by blocking these recognition sites HuR can stabilize its RNA interaction partners [71][72][73]. HuR is frequently upregulated in cancer cells and is known to be involved in many hallmarks of cancer, such as invasion, angiogenesis, and inflammation, by post-transcriptionally regulating various cancer-related mRNAs [71,72,[74][75][76]. HuR not only binds to protein-coding mRNA but also interacts with lncRNAs, thereby influencing their stability both in a positive and negative manner [55][56][57][58]77].…”

“…All four AUF1 isoforms form dimers and contain two tandem RRMs that include RNP sequence motifs [91]. Via these domains AUF1 primarily, but not exclusively, binds to U-rich RNA sequences of AREs, therefore competing with HuR [61,[71][72][73]85,91]. In addition, it has been found to bind to non-canonical U-rich and GU-rich sites [61,91].…”

“…Besides the two previously discussed examples HuR and AUF1, TTP is another RBP that binds to AREs, adenylate/uridylate-rich RNA motifs that function as signals for the rapid degradation of RNA [61,66,[71][72][73]85,91]. While HuR promotes the stability of RNAs by shielding these recognition sites, AUF1 recruits, upon binding to AREs, components of the RNA degradation machinery [71][72][73]91]. The exact components are not yet known [91].…”