title: Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion.
abstract: Our understanding of key epigenetic regulators involved in specific biological processes and cancers is still incomplete, despite great progress in genome-wide studies of the epigenome. Here, we carried out a systematic, genome-wide analysis of the functional significance of 615 epigenetic proteins in prostate cancer (PrCa) cells. We used the high-content cell-spot microarray technology and siRNA silencing of PrCa cell lines for functional screening of cell proliferation, survival, androgen receptor (AR) expression, histone methylation and acetylation. Our study highlights subsets of epigenetic enzymes influencing different cancer cell phenotypes. Plant homeo domain (PHD) finger proteins have a key role in cell survival and histone methylation, whereas histone deacetylases were primarily involved in regulating AR expression. In contrast, JumonjiC-domain (JmjC) containing histone lysine demethylases (KDMs) mainly had an impact on cell proliferation. Our results show that the KDMs JARID1B, PHF8, KDM3A, KDM3B and KDM4A were highly expressed in clinical PrCa samples. The PHD-finger protein 8 (PHF8), a transcriptional coactivator with both PHD- and JmjC-domains, was moderately to strongly expressed in 80% of clinical PrCa samples, whereas 76% of normal and benign samples were negative or only showed weak PHF8 expression. Strong PHF8 expression correlated significantly with high Gleason grade and was borderline significant for poor prognosis. The results of functional PHF8 knockdown implicate a role in cell migration and invasion, as shown by cell motility and 3-D invasion assays. Our study suggests that various cellular phenotypes are regulated by distinct subsets of epigenetic enzymes. Proteins interpreting and modifying histone methylation, such as JmjC-domain and particularly PHD-finger proteins like PHF8, are activated in subsets of PrCa's and promote cancer relevant phenotypes.
authors: Medical Biotechnology, VTT Technical Research Centre of Finland, and Center for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors: M
authors: M
authors: Björkman
authors: P
authors: P
authors: Östling
authors: V
authors: V
authors: Härmä
authors: J
authors: J
authors: Virtanen
authors: J-P
authors: JP
authors: Mpindi
authors: J
authors: J
authors: Rantala
authors: T
authors: T
authors: Mirtti
authors: T
authors: T
authors: Vesterinen
authors: M
authors: M
authors: Lundin
authors: A
authors: A
authors: Sankila
authors: A
authors: A
authors: Rannikko
authors: E
authors: E
authors: Kaivanto
authors: P
authors: P
authors: Kohonen
authors: O
authors: O
authors: Kallioniemi
authors: M
authors: M
authors: Nees
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics; D056466:Histone Demethylases / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000172:deficiency / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*
chemical_list: D011944:Receptors, Androgen; D014157:Transcription Factors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C511934:PHF8 protein, human; D006655:Histone Deacetylases