title: Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1).
abstract: Selected long noncoding RNAs (lncRNAs) have been shown to play important roles in carcinogenesis. Although the cellular functions of these transcripts can be diverse, many lncRNAs regulate gene expression. In contrast, factors that control the expression of lncRNAs remain largely unknown. Here we investigated the impact of RNA binding proteins on the expression of the liver cancer-associated lncRNA HULC (highly up-regulated in liver cancer). First, we validated the strong up-regulation of HULC in human hepatocellular carcinoma. To elucidate posttranscriptional regulatory mechanisms governing HULC expression, we applied an RNA affinity purification approach to identify specific protein interaction partners and potential regulators. This method identified the family of IGF2BPs (IGF2 mRNA-binding proteins) as specific binding partners of HULC. Depletion of IGF2BP1, also known as IMP1, but not of IGF2BP2 or IGF2BP3, led to an increased HULC half-life and higher steady-state expression levels, indicating a posttranscriptional regulatory mechanism. Importantly, HULC represents the first IGF2BP substrate that is destabilized. To elucidate the mechanism by which IGF2BP1 destabilizes HULC, the CNOT1 protein was identified as a novel interaction partner of IGF2BP1. CNOT1 is the scaffold of the human CCR4-NOT deadenylase complex, a major component of the cytoplasmic RNA decay machinery. Indeed, depletion of CNOT1 increased HULC half-life and expression. Thus, IGF2BP1 acts as an adaptor protein that recruits the CCR4-NOT complex and thereby initiates the degradation of the lncRNA HULC.
  
  
  CONCLUSIONS
  Our findings provide important insights into the regulation of lncRNA expression and identify a novel function for IGF2BP1 in RNA metabolism.
authors.affiliation: Helmholtz-University-Group "Molecular RNA Biology & Cancer," German Cancer Research Center DKFZ & Institute of Pathology, University Hospital Heidelberg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Hämmerle
authors.forename: Tony
authors.initials: T
authors.lastname: Gutschner
authors.forename: Hannah
authors.initials: H
authors.lastname: Uckelmann
authors.forename: Sevim
authors.initials: S
authors.lastname: Ozgur
authors.forename: Evgenij
authors.initials: E
authors.lastname: Fiskin
authors.forename: Matthias
authors.initials: M
authors.lastname: Gross
authors.forename: Britta
authors.initials: B
authors.lastname: Skawran
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Georg
authors.initials: G
authors.lastname: Stoecklin
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D011499:Protein Processing, Post-Translational; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: C528690:CNOT1 protein, human; C574685:HULC long non-coding RNA, human; C406144:IGF2BP1 protein, human; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; D014157:Transcription Factors