title: mRNA stability alterations mediated by HuR are necessary to sustain the fast growth of glioma cells.
abstract: Regulation of mRNA decay is an important mechanism controlling gene expression. Steady state levels of mRNAs can be markedly altered by changes in the decay rate. The control of mRNA stability depends on sequences in the transcript itself and on RNA-binding proteins that dynamically bind to these sequences. A well characterized sequence motif, which has been shown to be present in many short-lived mRNAs, is the de-stabilizing adenylate/uridylate-rich element (ARE) located at the 3' untranslated region (3'UTR) of mRNAs. HuR is an RNA-binding protein, which binds to AREs and in doing so, increases the half-life and steady state levels of the corresponding mRNA. Using tissue microarray technology, we found that HuR is over-expressed in human gliomas. We also found that there is a change in HuR localization from being solely in the nucleus to being expressed at high levels in the cytosol. Moreover, a positive correlation was found between total HuR levels, cytosolic localization and tumor grade. We also studied the decay rate of several HuR target mRNAs and found that these mRNAs have a slower rate of decay in glioma cell lines than in astrocytes. Finally, we have been able to decrease both the stability and steady state level of these transcripts in glioma cells using an RNA decoy. More importantly, the decoy transfected cells and cells exposed to a HuR inhibitor have reduced cell growth. In addition, pharmacological inhibition of HuR also resulted in glioma cell growth inhibition. In conclusion, our data suggest that post-transcriptional control abnormalities mediated by HuR are necessary to sustain the rapid growth of this devastating type of cancer.
authors.affiliation: Department of Neurosurgery, The Methodist Hospital and The Methodist Hospital Research Institute, Houston, TX 77030, USA. fbolognani@gmail.com
authors.forename: Federico
authors.initials: F
authors.lastname: Bolognani
authors.forename: Anne-Isabelle
authors.initials: AI
authors.lastname: Gallani
authors.forename: Lena
authors.initials: L
authors.lastname: Sokol
authors.forename: David S
authors.initials: DS
authors.lastname: Baskin
authors.forename: Nicole
authors.initials: N
authors.lastname: Meisner-Kober
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002458:Cell Fractionation / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007211:Indoles; D008297:Male; D040081:Protein Array Analysis / Q000379:methods; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D012720:Severity of Illness Index; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D051959:ELAV Proteins; D007211:Indoles; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C007293:DAPI; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human