Hu Antigen R (HuR) Protein Structure, Function and Regulation in Hepatobiliary Tumors

Abstract

Hu antigen R (HuR) is a 36-kDa ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), which plays an important role as a post-transcriptional regulator of specific RNAs under physiological and pathological conditions, including cancer. Herein, we review HuR protein structure, function, and its regulation, as well as its implications in the pathogenesis, progression, and treatment of hepatobiliary cancers. In particular, we focus on hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), tumors where the increased cytoplasmic localization of HuR and activity are proposed, as valuable diagnostic and prognostic markers. An overview of the main regulatory axes involving HuR, which are associated with cell proliferation, invasion, metastasis, apoptosis, and autophagy in HCC, is provided. These include the transcriptional, post-transcriptional, and post-translational modulators of HuR function, in addition to HuR target transcripts. Finally, whereas studies addressing the relevance of targeting HuR in CCA are limited, in the past few years, HuR has emerged as a potential therapeutic target in HCC. In fact, the therapeutic efficacy of some pharmacological inhibitors of HuR has been evaluated, in early experimental models of HCC. We, further, discuss the major findings and future perspectives of therapeutic approaches that specifically block HuR interactions, either with post-translational modifiers or cognate transcripts in hepatobiliary cancers.

Keywords: ELAV-like protein 1; RNA-binding protein; cholangiocarcinoma; hepatocellular carcinoma.

Figure 1

HuR domain organization, structures, and sequence alignment. (A) Schematic domain organization of human HuR. Black numbers indicate the residues flanking each domain. RNPs and residues flanking RNPs are colored in cyan. C13 and W261, implicated in dimerization, are highlighted in yellow. Susceptible lysines to become NEDDylated are highlighted in purple. N and C indicate N-terminal and C-terminal endings, respectively. (B) Ribbon structures of human HuR RRM domains. Side-chains of residues at RNPs are colored in cyan, those of C13 and W261 are highlighted in yellow; NEDDylated lysines are shown in purple. β-strands and α-helixes numbers are indicated. Left panel: NMR structure of RRM1 domain. Ten models are shown (PDB: 5SZW) [14]. Middle panel: X-ray structure of RRM12 tandem of HuR (PDB: 4ED5) [5]. Right panel: X-ray structure of RRM3 domain, in its dimeric form (PDB: 6GD1) [15]. (C) Sequence alignment of HuR, with homologous RNA binding proteins (ELAV, ELAVL-1, ELAVL-2, ELAVL-3, ELAVL-4, and PABP-4), from human and related organisms. Residues belonging to each RRM domain are shaded in grey. RNPs residues from HuR are highlighted in cyan, whereas C13 and W261 are in yellow. K283, K313, and K326 are highlighted in purple. Blue arrows represent β-strands, and red rectangles represent α-helixes of HuR.

Figure 2

Main regulatory axes involving HuR, which are associated with cell proliferation, invasion, metastasis, apoptosis, and autophagy during HCC. These include the transcriptional, post-transcriptional, and post-translational modulators of HuR function, in addition to HuR target transcripts.