title: Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors.
abstract: Histone deacetylases (HDACs) have emerged as important targets for cancer treatment. HDAC-inhibitors (HDACis) are well tolerated in patients and have been approved for the treatment of patients with cutaneous T-cell lymphoma (CTCL). To improve the clinical benefit of HDACis in solid tumors, combination strategies with HDACis could be employed. In this study, we applied Analysis of Functional Annotation (AFA) to provide a comprehensive list of genes and pathways affected upon HDACi-treatment in prostate cancer cells. This approach provides an unbiased and objective approach to high throughput data mining. By performing AFA on gene expression data from prostate cancer cell lines DU-145 (an HDACi-sensitive cell line) and PC3 (a relatively HDACi-resistant cell line) treated with HDACis valproic acid or vorinostat, we identified biological processes that are affected by HDACis and are therefore potential treatment targets for combination therapy. Our analysis revealed that HDAC-inhibition resulted among others in upregulation of major histocompatibility complex (MHC) genes and deregulation of the mitotic spindle checkpoint by downregulation of genes involved in mitosis. These findings were confirmed by AFA on publicly available data sets from HDACi-treated prostate cancer cells. In total, we analyzed 375 microarrays with HDACi treated and non-treated (control) prostate cancer cells. All results from this extensive analysis are provided as an online research source (available at the journal's website and at http://luigimarchionni.org/HDACIs.html). By publishing this data, we aim to enhance our understanding of the cellular changes after HDAC-inhibition, and to identify novel potential combination strategies with HDACis for the treatment of prostate cancer patients.
authors.affiliation: Department of Gynecology; Catharina Hospital Eindhoven; Eindhoven, The Netherlands; Prostate Cancer Program; Sidney Kimmel Comprehensive Cancer Center; Johns Hopkins University School of Medicine; Baltimore, MD USA; These authors contributed equally to this work.
authors.forename: Madeleine S Q
authors.initials: MS
authors.lastname: Kortenhorst
authors.forename: Michel D
authors.initials: MD
authors.lastname: Wissing
authors.forename: Ronald
authors.initials: R
authors.lastname: Rodríguez
authors.forename: Sushant K
authors.initials: SK
authors.lastname: Kachhap
authors.forename: Judith J M
authors.initials: JJ
authors.lastname: Jans
authors.forename: Petra
authors.initials: P
authors.lastname: Van der Groep
authors.forename: Henk M W
authors.initials: HM
authors.lastname: Verheul
authors.forename: Anuj
authors.initials: A
authors.lastname: Gupta
authors.forename: Paul O
authors.initials: PO
authors.lastname: Aiyetan
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Van Diest
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
mesh_terms: D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D014635:Valproic Acid; D006655:Histone Deacetylases
keywords: HDACis; analysis of functional annotation; gene expression analysis; major histocompatibility complex; mitotic spindle checkpoint; prostate cancer; valproic acid; vorinostat