TY - JOUR
T1 - MRNA stability alterations mediated by HuR are necessary to sustain the fast growth of glioma cells
AU - Bolognani, Federico
AU - Gallani, Anne Isabelle
AU - Sokol, Lena
AU - Baskin, David S.
AU - Meisner-Kober, Nicole
N1 - Funding Information:
Acknowledgments We thank Dr. Gregory N. Fuller, M.D. Anderson Cancer Center, Houston, Texas for providing the Tissue Micro-arrays used in the present studies, and Dr. Martyn A. Sharpe and Ms. Marsha Widmayer for critical reading of the manuscript. Funding for this research was generously provided by: Research Allocation Committee Grant, University of New Mexico School of Medicine and the Childhood Brain Tumor Foundation to FB, and The Henry J.N.Taub Fund for Neurological Research, The Pauline Sterne Wolff Memorial Foundation, Golfers Against Cancer, and the Methodist Hospital Foundation to DSB.
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/2
Y1 - 2012/2
N2 - 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 30 untranslated region (30UTR) of mRNAs. HuR is an RNAbinding 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.
AB - 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 30 untranslated region (30UTR) of mRNAs. HuR is an RNAbinding 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.
KW - Gliomas
KW - HuR
KW - mRNA stability
KW - RNA-binding protein
KW - Tissue microarray
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U2 - 10.1007/s11060-011-0707-1
DO - 10.1007/s11060-011-0707-1
M3 - Article
C2 - 21935689
AN - SCOPUS:84857044072
SN - 0167-594X
VL - 106
SP - 531
EP - 542
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 3
ER -