HuR-Mediated control of C/EBPβ mRNA stability and translation in ALK-Positive anaplastic large cell lymphomas

Abstract

The CCAAT/enhancer-binding protein β (C/EBPβ) plays a major role in the pathogenesis of anaplastic large cell lymphomas (ALCL) that express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase (ALK +). Although ALK-mediated C/EBPβ transcriptional activation has been reported, C/EBPβ mRNA possesses U-and AU-rich domains in its 3'-untranslated region (3'-UTR) thatmight be privileged targets for posttranscriptional control in ALK+ ALCLs. The purpose of this study was to explore this possibility. By using human ALCL-derived cells and a murine model of ALK-transformed cells, we show that the AU-binding protein HuR binds to the 3'-UTR of C/EBPβ mRNA, as previously reported in adipocytes, and that NPM-ALK enhances this interaction. Interaction betweenHuR andC/EBPβ mRNAimpacts on C/EBPβ gene expression at both themRNA and protein levels. Indeed, C/EBPβ mRNA stability following HuR silencing is reduced and reaches the value observed in ALK-inactivated cells. Remarkably, HuR expression is not modified by NPM-ALK, but its association with actively translating polysomes is dramatically increased in ALK+ cells.HuR/polysomes association diminisheswhenNPM-ALK activity is inhibited and is accompanied by a concomitant decrease of C/EBPβ mRNA translation. Finally, we show thatHuR andNPM-ALK colocalized in cytoplasmic granules and HuR is phosphroylated on tyrosine residues in ALK+ ALCL cells. Our study thus demonstrates that C/EBPβ is indeed regulated at the posttranscriptional level by HuR in ALK+ cells, leading us to propose that part ofNPM-ALK oncogenic properties relies on its ability tomodifyHuR properties in the cytoplasm and hence to alter expression of key actors of transformation. Mol Cancer Res; 9(4); 485-96. © 2011 American Association for Cancer Research.