title: Beta-catenin/HuR post-transcriptional machinery governs cancer stem cell features in response to hypoxia.
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-negative breast cancer cells, where the beta-catenin knockdown suppresses the stem cell phenotype in vitro and tumor growth in vivo. In such cells, we unravel the generalized involvement of the beta-catenin-driven machinery in the stabilization of EGF-induced mRNAs, including the cancer stem cell regulator IL6. Our study highlights the crucial role of post-transcriptional mechanisms in the maintenance/acquisition of cancer stem cell features and suggests that the hindrance of cytoplasmic beta-catenin function may represent an unprecedented strategy for targeting breast cancer stem/basal-like cells.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy ; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Gabriele
authors.initials: G
authors.lastname: D'Uva
authors.forename: Sara
authors.initials: S
authors.lastname: Bertoni
authors.forename: Mattia
authors.initials: M
authors.lastname: Lauriola
authors.forename: Sabrina
authors.initials: S
authors.lastname: De Carolis
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pacilli
authors.forename: Laura
authors.initials: L
authors.lastname: D'Anello
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.forename: Mario
authors.initials: M
authors.lastname: Taffurelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Montanaro
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafé
authors.forename: Gianluca
authors.initials: G
authors.lastname: Storci
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics; D054337:Cell Dedifferentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054682:Ribosome Subunits, Small, Eukaryotic / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D000951:Antigens, Neoplasm; D051959:ELAV Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C000604408:SNAI2 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D004815:Epidermal Growth Factor; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases