title: Systematic Analysis of AU-Rich Element Expression in Cancer Reveals Common Functional Clusters Regulated by Key RNA-Binding Proteins.
abstract: Defects in AU-rich elements (ARE)-mediated posttranscriptional control can lead to several abnormal processes that underlie carcinogenesis. Here, we performed a systematic analysis of ARE-mRNA expression across multiple cancer types. First, the ARE database (ARED) was intersected with The Cancer Genome Atlas databases and others. A large set of ARE-mRNAs was over-represented in cancer and, unlike non-ARE-mRNAs, correlated with the reversed balance in the expression of the RNA-binding proteins tristetraprolin (TTP, ZFP36) and HuR (ELAVL1). Serial statistical and functional enrichment clustering identified a cluster of 11 overexpressed ARE-mRNAs (CDC6, KIF11, PRC1, NEK2, NCAPG, CENPA, NUF2, KIF18A, CENPE, PBK, TOP2A) that negatively correlated with TTP/HuR mRNA ratios and was involved in the mitotic cell cycle. This cluster was upregulated in a number of solid cancers. Experimentally, we demonstrated that the ARE-mRNA cluster is upregulated in a number of tumor breast cell lines when compared with noninvasive and normal-like breast cancer cells. RNA-IP demonstrated the association of the ARE-mRNAs with TTP and HuR. Experimental modulation of TTP or HuR expression led to changes in the mitosis ARE-mRNAs. Posttranscriptional reporter assays confirmed the functionality of AREs. Moreover, TTP augmented mitotic cell-cycle arrest as demonstrated by flow cytometry and histone H3 phosphorylation. We found that poor breast cancer patient survival was significantly associated with low TTP/HuR mRNA ratios and correlated with high levels of the mitotic ARE-mRNA signature. These results significantly broaden the role of AREs and their binding proteins in cancer, and demonstrate that TTP induces an antimitotic pathway that is diminished in cancer. Cancer Res; 76(14); 4068-80. ©2016 AACR.
authors.affiliation: Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Edward
authors.initials: E
authors.lastname: Hitti
authors.affiliation: Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Tala
authors.initials: T
authors.lastname: Bakheet
authors.affiliation: Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Norah
authors.initials: N
authors.lastname: Al-Souhibani
authors.affiliation: Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Walid
authors.initials: W
authors.lastname: Moghrabi
authors.affiliation: Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Suhad
authors.initials: S
authors.lastname: Al-Yahya
authors.affiliation: Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Maha
authors.initials: M
authors.lastname: Al-Ghamdi
authors.affiliation: Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Maher
authors.initials: M
authors.lastname: Al-Saif
authors.affiliation: Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Shoukri
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Lánczky
authors.affiliation: Centre Scientifique de Monaco Biomedical Department, Monaco, Principality of Monaco.
authors.forename: Renaud
authors.initials: R
authors.lastname: Grépin
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: University of Nice, Institute for research on cancer and aging of Nice (IRCAN), Nice, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagès
authors.affiliation: Molecular BioMedicine Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. khabar@kfshrc.edu.sa.
authors.forename: Khalid S A
authors.initials: KS
authors.lastname: Khabar
mesh_terms: D000225:Adenine / Q000032:analysis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D000067780:ELAV-Like Protein 1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D026723:Polyadenylation; D012333:RNA, Messenger / Q000032:analysis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051816:Tristetraprolin / Q000235:genetics; D014529:Uridine / Q000032:analysis
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D000225:Adenine; D014529:Uridine