Abstract
AU-rich element-binding proteins (AUBPs) represent important post-transcriptional regulators of gene expression. AUBPs can bind to the AU-rich elements present in the 3’-UTR of more than 8% of all mRNAs and are thereby able to control the stability and/or translation of numerous target mRNAs. The regulation of the stability and the translation of mRNA transcripts by AUBPs are highly complex processes that occur through multiple mechanisms depending on the cell type and the cellular context. While AUBPs have been shown to be involved in inflammatory processes and the development of various cancers, their important role and function in the development of chronic metabolic and inflammatory fatty liver diseases (FLDs), as well as in the progression of these disorders toward cancers such as hepatocellular carcinoma (HCC), has recently started to emerge. Alterations of either the expression or activity of AUBPs are indeed significantly associated with FLDs and HCC, and accumulating evidence indicates that several AUBPs are deeply involved in a significant number of cellular processes governing hepatic metabolic disorders, inflammation, fibrosis, and carcinogenesis. Herein, we discuss our current knowledge of the roles and functions of AUBPs in liver diseases and cancer. The relevance of AUBPs as potential biomarkers for different stages of FLD and HCC, or as therapeutic targets for these diseases, are also highlighted.
Highlights
Hepatic metabolic disorders and cancers account for more than 3.5% of deaths worldwide [1]
In addition to directly acting on their target mRNAs, noncoding RNAs (ncRNAs) have been shown to significantly interfere with the activity of AU-rich element-binding proteins (AUBPs) by either (i) competing for target binding, (ii) facilitating AUBP binding to their target, (iii) destabilizing the mRNAs of AUBPs, or (iv) indirectly inducing post-translational modifications of AUBPs (Figure 4)
Indirect mechanisms regulating the activity of AUBPs can be under the control of long noncoding RNAs (lncRNAs) or circRNAs. Examples of such indirect regulation are illustrated by (i) the lncRNA highly upregulated in liver cancer (HULC), which triggers Y-box-binding protein 1 (YB-1) phosphorylation by the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinases, thereby impairing its binding to mRNAs [69]; (ii) the lncRNA MIR22HG, which binds to HuR and prevents its translocation to the cytoplasm and its binding to oncogenes (e.g., CTNNB1, CCNB1, HIF1A, PTGS2, and FOS) in SMMC-7721 cells [70]; (iii) the lncRNA pleiotrophin downstream transcript (Ptn-dt), which sequesters HuR from miR-96, affecting the stability of this miRNA [71]; (iv) the circRNA circBACH1, which binds to HuR and regulates its translocation into the cytoplasm in Hep3B and HepG2 cells [72]
Summary
Hepatic metabolic disorders and cancers account for more than 3.5% of deaths worldwide [1]. Most cases of HCC usually arise in a cirrhotic context, but recent evidence indicates that up to 20% of cases develop in the absence of cirrhosis when only steatosis and/or inflammation is present [5] This is the case in nonalcoholic fatty liver disease (NAFLD), whose incidence is constantly on the rise and is. The mRNAs stored in SGs are protected from proteasomal degradation during cellular stress and can be later released and translated into proteins [20] This results in transcript stabilization, along with a transient inhibition of translation [20]. WwiainnhinthihdSciGhbtthifsrtaeaiaocnfirnalseicltaotaptfttreehodtsatrmetaicnnTRtsteTNoldPaAtpfiironrdoondemtuge[rci2pnat0idrso]o.ant[tSe2imoao0ns]ma.o,yuemTophaAcoilcsnUdutBrerregPatshnrsua,rsldoftsosuaurtgmciinohhinnttahgrdseagunCTrrsoiGUcnwrFgGitp–hcβttefr/alsSilcptumtalolbeaartirdl(iTrszpetGarpateFtiesho)as–nwtβa,aR1naydNslto[iA3cmna1-gnu,b3liw2ban]ted.iitoiTlhnanTgt,aePcropthnrrraeaoslsinteseasatieilnsesnenotd1t (CUGBP1) or CUGBP2, despite not being the central structural proteins required for SG formation, have the ability to bind and to stabilize transcripts by associating with SGs, transiently impairing their translation [26] (Figure 3). Diverse hypotheses involving protein and mRNA shuttling, as well as a potential merge between SGs and PBs, have been raised, but the precise mechanisms driving P-body and SG aInsts. eJ.mMboll.yS,cai.s20w20e,l2l1a,sx tFhOeRirPfEuEnRcRtEioVnIEaWl relevance, remain to be precisely defined [35,36]
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