title: The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression.
abstract: Epigenetic silencing of tumour suppressor genes is an important mechanism involved in cell transformation and tumour progression. The Set and RING-finger-associated domain-containing protein UHRF1 might be an important link between different epigenetic pathways. Here, we report that UHRF1 is frequently overexpressed in human prostate tumours and has an important role in prostate cancer pathogenesis and progression. Analysis of human prostate cancer samples by microarrays and immunohistochemistry showed increased expression of UHRF1 in about half of the cases. Moreover, UHRF1 expression was associated with reduced overall survival after prostatectomy in patients with organ-confined prostate tumours (P < 0.0001). UHRF1 expression was negatively correlated with several tumour suppressor genes and positively with the histone methyltransferase (HMT) EZH2 both in prostate tumours and cell lines. UHRF1 knockdown reduced proliferation, clonogenic capability and anchorage-independent growth of prostate cancer cells. Depletion of UHRF1 resulted in reactivation of several tumour suppressor genes. Gene reactivation upon UHRF1 depletion was associated with changes in histone H3K9 methylation, acetylation and DNA methylation, and impaired binding of the H3K9 HMT Suv39H1 to the promoter of silenced genes. Co-immunoprecipitation experiments showed direct interaction between UHRF1 and Suv39H1. Our data support the notion that UHRF1, along with Suv39H1 and DNA methyltransferases, contributes to epigenetic gene silencing in prostate tumours. This could represent a parallel and convergent pathway to the H3K27 methylation catalyzed by EZH2 to synergistically promote inactivation of tumour suppressor genes. Deregulated expression of UHRF1 is involved in the prostate cancer pathogenesis and might represent a useful marker to distinguish indolent cancer from those at high risk of lethal progression.
authors.affiliation: Department of Structural and Functional Biology, University of Insubria, Via A da Giussano 12, Busto Arsizio, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Babbio
authors.forename: C
authors.initials: C
authors.lastname: Pistore
authors.forename: L
authors.initials: L
authors.lastname: Curti
authors.forename: I
authors.initials: I
authors.lastname: Castiglioni
authors.forename: P
authors.initials: P
authors.lastname: Kunderfranco
authors.forename: L
authors.initials: L
authors.lastname: Brino
authors.forename: P
authors.initials: P
authors.lastname: Oudet
authors.forename: R
authors.initials: R
authors.lastname: Seiler
authors.forename: G N
authors.initials: GN
authors.lastname: Thalman
authors.forename: E
authors.initials: E
authors.lastname: Roggero
authors.forename: M
authors.initials: M
authors.lastname: Sarti
authors.forename: S
authors.initials: S
authors.lastname: Pinton
authors.forename: M
authors.initials: M
authors.lastname: Mello-Grand
authors.forename: G
authors.initials: G
authors.lastname: Chiorino
authors.forename: C V
authors.initials: CV
authors.lastname: Catapano
authors.forename: G M
authors.initials: GM
authors.lastname: Carbone
authors.forename: I M
authors.initials: IM
authors.lastname: Bonapace
mesh_terms: D000107:Acetylation; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases