title: The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets.
abstract: Previously, we identified the stress-induced chaperone, Hsp27, as highly overexpressed in castration-resistant prostate cancer and developed an Hsp27 inhibitor (OGX-427) currently tested in phase I/II clinical trials as a chemosensitizing agent in different cancers. To better understand the Hsp27 poorly-defined cytoprotective functions in cancers and increase the OGX-427 pharmacological safety, we established the Hsp27-protein interaction network using a yeast two-hybrid approach and identified 226 interaction partners. As an example, we showed that targeting Hsp27 interaction with TCTP, a partner protein identified in our screen increases therapy sensitivity, opening a new promising field of research for therapeutic approaches that could decrease or abolish toxicity for normal cells. Results of an in-depth bioinformatics network analysis allying the Hsp27 interaction map into the human interactome underlined the multifunctional character of this protein. We identified interactions of Hsp27 with proteins involved in eight well known functions previously related to Hsp27 and uncovered 17 potential new ones, such as DNA repair and RNA splicing. Validation of Hsp27 involvement in both processes in human prostate cancer cells supports our system biology-predicted functions and provides new insights into Hsp27 roles in cancer cells.
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France;
authors.forename: Maria
authors.initials: M
authors.lastname: Katsogiannou
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France;
authors.forename: Claudia
authors.initials: C
authors.lastname: Andrieu
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France;
authors.forename: Virginie
authors.initials: V
authors.lastname: Baylot
authors.affiliation: ¶Aix-Marseille Université, F-13284, Marseille, France; **Institut de Mathématiques de Marseille, CNRS UMR7373, Marseille, F-13009, France;
authors.forename: Anaïs
authors.initials: A
authors.lastname: Baudot
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France;
authors.forename: Nelson J
authors.initials: NJ
authors.lastname: Dusetti
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France;
authors.forename: Odile
authors.initials: O
authors.lastname: Gayet
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France;
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: ‡‡Inserm U866, Faculty of Medicine, 21000 Dijon, France; §§CGFL Dijon, France;
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France;
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France;
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: ¶Aix-Marseille Université, F-13284, Marseille, France; ¶¶TAGC Inserm U1090, Marseille, F-13009, France; ‖‖CNRS, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Brun
authors.affiliation: From the ‡Inserm, UMR1068, CRCM, Marseille, F-13009, France; §Institut Paoli-Calmettes, Marseille, F-13009, France; ¶Aix-Marseille Université, F-13284, Marseille, France; ‖CNRS, UMR7258, CRCM, Marseille, F-13009, France; palma.rocchi@inserm.fr.
authors.forename: Palma
authors.initials: P
authors.lastname: Rocchi
mesh_terms: D017398:Alternative Splicing; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D004260:DNA Repair; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D018832:Molecular Chaperones; D058990:Molecular Targeted Therapy; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000090324:Tumor Protein, Translationally-Controlled 1; D020798:Two-Hybrid System Techniques
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009841:Oligonucleotides; C000715647:TPT1 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1; C000595177:apatorsen