title: Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer.
abstract: Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers.
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Vahid
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Daksh
authors.initials: D
authors.lastname: Thaper
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kate F
authors.initials: KF
authors.lastname: Gibson
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bishop
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006360:Heat-Shock Proteins; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D018832:Molecular Chaperones; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins; C057725:HSPB1 protein, human; C551991:WWTR1 protein, human; C088374:YAP1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases