Targeting the Multifaceted HuR Protein, Benefits and Caveats

Abstract

The RNA-binding protein (RBP) HuR is one of the most widely studied regulators of the eukaryotic posttranscriptional gene expression and it plays a physiological role in mediating the cellular response to apoptotic, proliferating and survival stimuli. Following physiological or stress stimuli, HuR protein binds to Adenylate-Urydinilate rich elements (AREs) generally contained in the 3'UTR of transcripts, then it shuttles from the nucleus to the cytoplasm and regulates the half-life and/or translation of cargo mRNAs. Derangements in sub-cellular localization and expression of HuR have been associated with the pathophysiology of many diseases and this protein has been proposed as a potential drug target. Recent findings also re-evaluated HuR as a splicing and polyadenylation factor, expanding its spectrum of functional activity up to the maturation of pre-mRNAs. In this review, we generate a comprehensive picture of HuR functionality to discuss the implications of considering HuR as pharmacological target and the detrimental or positive impact that can be expected upon its modulation. Firstly, we focus on the recent findings about the mechanistic role of HuR in the nucleus and in the regulation of long non coding RNAs; then we describe the animal models and the clinical association and significance in cancer; finally, we have reviewed the pharmacological tools that influence HuR's post-transcriptional control and the efforts made to identify specific HuR inhibitors.

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

“…CRC tumors have a disproportionate level of tumor promoting genes expressed that contain AREs within their 3′UTRs [33], and many of these mRNA transcripts have been shown to be bound and regulated by the RNA binding protein HuR [19]. Previous work in our lab demonstrated that cytoplasmic HuR localization is observed in 76% of colorectal adenomas and 94% of colorectal adenocarcinomas [12].…”

“…Moreover, increased HuR expression and cytoplasmic localization in tumors correlate with poor disease prognosis and advanced tumor staging [12, 48–51]. Thus, there are many data points from multiple laboratories over various tumor types that HuR is a strong candidate target in cancer [7, 18, 19, 52]. In this study, MS444 is used here as a tool compound for proof-of-principle for pharmacological HuR inhibition, and that targeting HuR with MS-444 has anti-tumor activity as a monotherapy in multiple pre-clinical models for CRC.…”

Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy

“…[13] This is the first application of pharmacological inhibition of HuR in cardiac myocytes, and given the high recent interest in developing a pharmacological inhibitor of HuR for therapeutic use [13,25-27], represents a potential means for long-term translation of these basic science findings. Importantly, HuR knockdown or inhibition in basal/resting NRVMs appears to have very little effect.…”

The Ribonucleic Complex HuR-MALAT1 Represses CD133 Expression and Suppresses Epithelial–Mesenchymal Transition in Breast Cancer

“…The human antigen R (HuR; or ELAV1) is a member of the embryonic lethal abnormal vision RNA-binding protein family, known to regulate the half-life of target mRNAs (17). Initially identified as an mRNA export factor (18), its main nuclear functions are regulation of splicing, mRNA processing, and polyadenylation (19).…”