Beta-CateninHuR Post-Transcriptional Machinery Governs Cancer Stem Cell Features in Response to Hypoxia.docVIP

Beta-Catenin/HuR Post-Transcriptional Machinery Governs Cancer Stem Cell Features in Response to Hypoxia 1,2* Gabriele D’Uva , Sara Bertoni 1,3 2 1 1,4 , Mattia Lauriola , Sabrina De Carolis , Annalisa Pacilli , Laura D’Anello , Donatella Santini , Mario Taffurelli , Claudio Ceccarelli 1,3 1 5 1 , Yosef Yarden , Lorenzo Montanaro , 2 1 Massimiliano Bonafé1,3*?, Gianluca Storci1,3*? 1 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy, 2 Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel, 3 Center for Applied Biomedical Research (CRBA) S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy, 4 Centro Interdipartimentale di Ricerche sul Cancro Giorgio Prodi-CIRC, University of Bologna, Bologna, Italy, 5 Clinical and Surgical Science, University of Bologna, Bologna, Italy Abstract Hypoxia has been long-time acknowledged as major cancer-promoting microenvironment. In such an energy- restrictive condition, post-transcriptional mechanisms gain importance over the energy-expensive gene transcription machinery. Here we show that the onset of hypoxia-induced cancer stem cell features requires the beta-catenin- dependent post-transcriptional up-regulation of CA9 and SNAI2 gene expression. In response to hypoxia, beta- catenin moves from the plasma membrane to the cytoplasm where it binds and stabilizes SNAI2 and CA9 mRNAs, in cooperation with the mRNA stabilizing protein HuR. We also provide evidence that the post-transcriptional activity of cytoplasmic beta-catenin operates under normoxia in basal-like/triple-negati