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Heat-Shock Factor 2 Is a Suppressor of Prostate Cancer Invasion

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Heat-Shock Factor 2 Is a Suppressor of Prostate Cancer Invasion Oncogene (2016) 35, 1770–1784 OPEN © 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16 www.nature.com/onc ORIGINAL ARTICLE Heat-shock factor 2 is a suppressor of prostate cancer invasion JK Björk1,2,4, M Åkerfelt1,2,4, J Joutsen1,3, MC Puustinen1,3, F Cheng1,3, L Sistonen1,3,4 and M Nees1,4 Heat-shock factors (HSFs) are key transcriptional regulators in cell survival. Although HSF1 has been identified as a driver of carcinogenesis, HSF2 has not been explored in malignancies. Here, we report that HSF2 suppresses tumor invasion of prostate cancer (PrCa). In three-dimensional organotypic cultures and the in vivo xenograft chorioallantoic membrane model HSF2 knockdown perturbs organoid differentiation and promotes invasiveness. Gene expression profiling together with functional studies demonstrated that the molecular mechanism underlying the effect on tumor progression originates from HSF2 steering the switch between acinar morphogenesis and invasion. This is achieved by the regulation of genes connected to, for example, GTPase activity, cell adhesion, extracellular matrix and actin cytoskeleton dynamics. Importantly, low HSF2 expression correlates with high Gleason score, metastasis and poor survival of PrCa patients, highlighting the clinical relevance of our findings. Finally, the study was expanded beyond PrCa, revealing that the expression of HSF2 is decreased in a wide range of cancer types. This study provides the first evidence for HSF2 acting as a suppressor of invasion in human malignancies. Oncogene (2016) 35, 1770–1784; doi:10.1038/onc.2015.241; published online 29 June 2015 INTRODUCTION HSF1 was highlighted in a cohort of breast cancer patients, Prostate cancer (PrCa) is the most commonly diagnosed male showing correlation between high HSF1 expression and 15 cancer in Western countries.1 Gleason grading, which is based on decreased survival. Recently, HSF1-regulated transcriptional glandular differentiation patterns within tumor biopsies, remains programs in malignant cells of several cancer types, and in tumor the standard for assessing prognosis and treatment.2 Although stroma, were reported to be different from the classical stress 16,17 primary PrCa is often indolent, advanced PrCa can metastasize response. both locally and distantly. As PrCa progresses, it becomes resistant In contrast to HSF1, another HSF family member HSF2, which can 12,18–21 to pharmacological and surgical treatments and castration- modulate HSF1-mediated stress responses, has hitherto not resistant PrCa develops,1 which remains lethal. been associated with cancer. Genome-wide analyses revealed that The aggressiveness of cancer is connected to its invasive HSF2 has an active role during mitosis, as it binds numerous loci in properties, which are governed by signaling pathways regulating the human genome, despite global repression of the chromatin 12 dynamics of the cytoskeleton and turnover of cell–matrix and environment. Furthermore, decreased HSF2 expression during cell–cell junctions.3 The dynamics of cytoskeletal microfilaments mitosis was shown to protect cells against proteotoxicity and 22 is directed by plasma membrane receptors, including receptor apoptosis. Several cell lines, predominantly of tumorigenic origin, tyrosine kinases, G-protein coupled receptors, integrins, transform- downregulate HSF2 expression during mitosis, perhaps correlating β with the elevated levels of proteotoxic stress that cancer cells are ing growth factor- receptors, E-cadherins and Frizzled proteins. 22,23 The cognate receptors activate members of the RHO GTPase subjected to, thereby giving the cells a survival advantage. family, which modulate effector protein activity.4 In PrCa studies, Here, we demonstrate that HSF2 acts as a potent suppressor of G-protein signaling and downstream pathway dynamics coincide tumor progression and invasion in PrCa by regulating signaling with actin cytoskeleton reorganization, formation of invadopodia, pathways steering epithelial plasticity. Furthermore, results from extracellular matrix (ECM) degradation, modulations in adhesion patient material imply functions of HSF2 in several human – fi and collagen contraction.4 7 Molecular characterization of the malignancies. Our ndings strongly connect HSF2 to cancer and transition from stable acinar morphology to local invasion, that is, invasion, and advocate the use of HSF2-mediated regulation in the invasive switch, is inconclusive but needed as it may provide therapeutics. means to predict PrCa progression and facilitate discovery of treatments. RESULTS Heat-shock factors (HSFs) are multifaceted transcription factors that regulate the response upon proteotoxic stress, that is, the Decreased HSF2 expression corresponds to high Gleason score heat-shock response. HSF1 is the master regulator of stress and metastasis in PrCa patient samples responses and its targets include molecular chaperones, which To explore a role of HSF2 in human malignancy, we analyzed maintain protein homeostasis.8,9 HSF1 also regulates genes HSF2 mRNA expression in a transcriptomic data set from 216 involved in, for example, cell cycle, protein synthesis, ribosome clinical PrCa samples.24 Interestingly, reduced HSF2 expression biogenesis and glucose metabolism.10–12 Importantly, HSF1 was found in PrCa samples compared with normal samples, promotes cancer cell survival.10,13,14 The clinical significance of and the expression was further decreased in metastatic 1Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; 2Medical Biotechnology, VTT Technical Research Centre of Finland, Turku, Finland and 3Department of Biosciences, Åbo Akademi University, Turku, Finland. Correspondence: Professor L Sistonen or Dr M Nees, Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu 6, Turku 20520, Finland. E-mail: lea.sistonen@abo.fi or matthias.nees@btk.fi 4These authors contributed equally to this work. Received 3 November 2014; revised 2 April 2015; accepted 22 May 2015; published online 29 June 2015 Role of HSF2 in prostate cancer JK Björk et al 1771 HSF2 20% PTEN 18% 200 TP53 29% MYC 60% HSF1 20% Homozygous mRNA mRNA Amplification Mutation 150 deletion downregulation upregulation HSF2 PTEN HSF1 5 4 4 8 als als 100 als 3 2 HSF2 expression (log2) 6 2 0 1 4 0 -2 2 -1 -4 -2 0 -6 mRNA expression mRNA mRNA expression mRNA mRNA expression mRNA -3 Z-scores vs norm Z-scores vs norm Z-scores vs norm -2 -4 -8 NormalCancer Neg SMPos SM MetastasisGleason:Gleason: 6 Gleason: 7 Gleason: 8 9 Neg SVPos inv SV inv Gain Gain Amp LN inv normal Homdel Hetloss Diploid Homdel Hetloss Diploid Hetloss Diploid LN inv abnormal Putative copy-number Putative copy-number Putative copy-number alterations (RAE) alterations (RAE) alterations (RAE) Figure 1. Low HSF2 expression correlates with aggressiveness of PrCa in human clinical samples. (a) Decreased HSF2 expression correlates with advanced PrCa. Analysis of mRNA expression for HSF2 in data sets from human PrCa (MSKCC),24 indicating that HSF2 expression is decreased in PrCa compared with normal tissue, and further decreased in advanced PrCa (Gleason score ⩾ 8), metastases, lymph node invasion (LN inv abnormal), positive surgical margins (SM) and positive seminal vesicle invasion (SV inv). (b) Oncoprints of HSF2, PTEN, TP53, MYC and HSF1 across 85 PrCa tumors,24 indicating genomic alterations. Individual genes are represented in each row, and individual tumors are represented as columns. Genetic alterations are color coded: dark blue, homozygous deletion; red, amplification; light blue frame, mRNA downregulation; pink frame, mRNA upregulation; green square, mutation. The oncoprints are based on data obtained from the cBioPortal for Cancer Genomics (http://www.cbioportal.org/public-portal/). Z-score threshold ± 2. (c) Box and whisker plots indicating the expression of HSF2, PTEN or HSF1 mRNA across different subsets of PrCa tumors divided by the putative DNA copy-number status. Homdel, homozygous deletion; hetloss, heterozygous deletion; diploid, no change; gain, moderate amplification; amp, high-level amplification. HSF2 mRNA expression is as expected progressively lower across the different subgroups of PrCa with HSF2 ploidy status ranging from gain to homozygous deletion. Note that the scales for copy-number status (x axis) and mRNA expression (y axis) differ between the three graphs. The mRNA z-scores are compared with the expression in normal prostate samples. RAE, RAE algorithm. samples (Figure 1a). At closer examination, low HSF2 expression validates the biological relevance of decreased expression correlated with high Gleason score tumors (Gleason scores ⩾ 8), observed in high-grade Gleason primary tumors. which are prone to progress to castration-resistant PrCa and form distant metastases, as well as are associated with therapy failure 1 HSF2 levels decline as PrCa cells advance towards an invasive and overall poor patient outcome. Concurrently, low HSF2 phenotype and display dynamic expression during organotypic expression was associated with lymph node invasion, positive development surgical margins and positive seminal vesicle invasion (Figure 1a), To investigate the molecular function of HSF2 in PrCa, we all indicating suppressive capacity of HSF2 on invasion/metastasis. analyzed the mRNA expression in a panel of human prostate cell The relevance of altered HSF2 expression was elucidated by 5 comparing the genomic profile with that of known tumor lines with different malignant potential and invasive behavior.
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