title: Tumor-secreted Hsp90 subverts polycomb function to drive prostate tumor growth and invasion.
abstract: Prostate cancer remains the second highest contributor to male cancer-related lethality. The transition of a subset of tumors from indolent to invasive disease is associated with a poor clinical outcome. Activation of the epithelial to mesenchymal transition (EMT) genetic program is a major risk factor for cancer progression. We recently reported that secreted extracellular Hsp90 (eHsp90) initiates EMT in prostate cancer cells, coincident with its enhanced expression in mesenchymal models. Our current work substantially extended these findings in defining a pathway linking eHsp90 signaling to EZH2 function, a methyltransferase of the Polycomb repressor complex. EZH2 is also implicated in EMT activation, and its up-regulation represents one of the most frequent epigenetic alterations during prostate cancer progression. We have now highlighted a novel epigenetic function for eHsp90 via its modulation of EZH2 expression and activity. Mechanistically, eHsp90 initiated sustained activation of MEK/ERK, a signal critical for facilitating EZH2 transcriptional up-regulation and recruitment to the E-cadherin promoter. We further demonstrated that an eHsp90-EZH2 pathway orchestrates an expanded repertoire of EMT-related events including Snail and Twist expression, tumor cell motility, and anoikis resistance. To evaluate the role of eHsp90 in vivo, eHsp90 secretion was stably enforced in a prostate cancer cell line resembling indolent disease. Remarkably, eHsp90 was sufficient to induce tumor growth, suppress E-cadherin, and initiate localized invasion, events that are exquisitely dependent upon EZH2 function. In summary, our findings illuminate a hitherto unknown epigenetic function for eHsp90 and support a model wherein tumor eHsp90 functions as a rheostat for EZH2 expression and activity to orchestrate mesenchymal properties and coincident aggressive behavior.
authors: From the Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425 and.
authors: Krystal D
authors: KD
authors: Nolan
authors: the Department of Urology and Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors: Omar E
authors: OE
authors: Franco
authors: From the Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425 and.
authors: Michael W
authors: MW
authors: Hance
authors: the Department of Urology and Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors: Simon W
authors: SW
authors: Hayward
authors: From the Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425 and isaacsj@musc.edu.
authors: Jennifer S
authors: JS
authors: Isaacs
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D047368:Tumor Burden
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018841:HSP90 Heat-Shock Proteins; D063146:Polycomb-Group Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: Cadherin-1 (CDH1); Epigenetics; Epithelial Cadherin (E-cadherin); Epithelial-Mesenchymal Transition (EMT); Extracellular Signal-regulated Kinase (ERK); Heat Shock Protein 90 (Hsp90); Histone Methylation; Polycomb; Prostate Cancer; Tumor Invasion; ezh2