The RNA-binding protein HuR in human cancer: A friend or foe?

Abstract

The RNA-binding proteins (RBPs) are critical trans factors that associate with specific cis elements present in mRNAs whose stability and translation are subject to regulation. The RBP Hu antigen R (HuR) is overexpressed in a wide variety of human cancers and serves as a prognostic factor of poor clinical outcome. HuR promotes tumorigenesis by interacting with a subset of oncogenic mRNAs implicated in different cancer hallmarks, and resistance to therapy. Reduction of HuR levels in cancer cells leads to tumor regression in mouse xenograft models. These findings prompt a working model whereby cancer cells use HuR, a master switch of multiple oncogenic mRNAs, to drive drug resistance and promote cell survival and metastasis, thus rendering the tumor cells with high cytoplasmic HuR more progressive and resistant to therapy. This review summarizes the roles of HuR in cancer and other diseases, therapeutic potential of HuR inhibition, and the current status of drug discovery on HuR.

Keywords: Cancer; Companion assay; Drug development; Drug discovery; Drug resistance; HuR; Molecular therapy; RNA-binding protein; Small molecules.

Figure 1:

Schematic structure of HuR. HuR protein consists of 326 amino acids (aa). It has three conserved RNA recognition motifs (RRMs) and an unconserved hinge region containing HuR nucleocytoplasmic shuttling (HNS) sequence. The amino acid positions of these regions are indicated. RRM1 and RRM2 are responsible for recognizing and binding to AREs of mRNA targets. RRM3 is involved in binding to poly(A) tail of mRNA targets and HuR multimerization on mRNA targets. The hinge domain mainly controls the nuclear and cytoplasmic shuttling of HuR. The major post-translational modified amino acids along with the corresponding enzymes are indicated as well, with phosphorylated amino acids and corresponding kinases in black and other modified amino acids and enzymes in grey.

Figure 2:

Map of the regulators of HuR at different levels. Transcriptional factor NF-κB and Smad family proteins regulate the transcription of HuR. RNA-binding protein RNPC1 (green, up-regulation) and TTP (red, down-regulation) oppositely regulate the stability of HuR mRNA, while HuR also autoregulates its own mRNA. MicroRNAs that bind to HuR mRNA and suppress the translation of HuR are listed in red rounded rectangle. Post-translational regulators of HuR are listed in rectangles, with enzymes modulating HuR localization and binding affinity in grey rectangles, MDM2 upregulating HuR expression in green rectangle, and E3 ligases promoting HuR degradation in red rectangle.

Figure 3:

Schematic diagram of strategies for targeting HuR. There are three major strategies used for inhibition of HuR: inhibition of HuR expression by RNA interference, inhibition of HuR cytoplasmic translocation and inhibition of HuR–RNA interaction by small molecular compounds. Company assay can be used in parallel to monitor the outcomes of targeting HuR.