title: The RNA-binding protein HuR promotes glioma growth and treatment resistance.
abstract: Posttranscriptional regulation is a critical control point for the expression of genes that promote or retard tumor growth. We previously found that the mRNA-binding protein, ELAV 1 (HuR), is upregulated in primary brain tumors and stabilizes growth factor mRNAs such as VEGF and IL-8. To better understand the role of HuR in brain tumor growth, we altered levels of HuR in glioma cells by short hairpin RNA or ectopic expression and measured tumor cell phenotype using in vitro and in vivo models. In HuR-silenced cells, we found a significant decrease in anchorage-independent growth and cell proliferation with a concomitant induction of apoptosis. Using an intracranial tumor model with primary glioblastoma cells, HuR silencing produced a significant decrease in tumor volume. In contrast, overexpression of HuR produced in vitro chemoresistance to standard glioma therapies. Because bcl-2 is abundantly expressed in glioma and associated with tumor growth and survival, we determined the impact of HuR on its regulation as a molecular validation to the cellular and animal studies. Using UV cross-linking and RNA immunoprecipitation, we show that HuR bound to the 3'-untranslated region of all bcl-2 family members. Silencing of HuR led to transcript destabilization and reduced protein expression. Polysome profiling indicated loss of HuR from the translational apparatus. In summary, these findings reveal a HuR-dependent mechanism for cancer cell survival and sensitivity to chemotherapeutic drugs suggesting that HuR should be considered as a new therapeutic target.
authors.affiliation: Department of Neurology, Division of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Filippova
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Yang
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wang
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.forename: Cathy
authors.initials: C
authors.lastname: Langford
authors.forename: Peter H
authors.initials: PH
authors.lastname: King
authors.forename: Crystal
authors.initials: C
authors.lastname: Wheeler
authors.forename: L Burt
authors.initials: LB
authors.lastname: Nabors
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; C052617:Bcl2 protein, mouse; D020169:Caspases