title: A role for the WWOX gene in prostate cancer.
abstract: Expression of the WWOX gene, encompassing the common chromosome fragile site FRA16D, is altered in a large fraction of cancers of various types, including prostate cancer. We have examined expression and biological functions of WWOX in prostate cancer. WWOX mRNA and protein expression were significantly reduced in prostate cancer-derived cells (LNCaP, DU145, and PC-3) compared with noncancer prostate cells (PWR-1E), and WWOX expression was reduced in 84% of prostate cancers, as assessed by immunohistochemical staining. Down-modulation of WWOX expression in the prostate cancer-derived cells is due to DNA hypermethylation in the WWOX regulatory region. Treatment with 5-aza-2'-deoxycytidine (AZA), a DNA methyltransferase inhibitor, and trichostatin A, a histone deacetylase inhibitor, led to increased WWOX mRNA and protein expression in prostate cancer-derived cells, most strikingly in DU145 cells. Transfection-mediated WWOX overexpression in DU145 cells suppressed colony growth (P = 0.0012), and WWOX overexpression by infection with Ad-WWOX virus induced apoptosis through a caspase-dependent mechanism and suppressed cell growth. Lastly, ectopic expression of WWOX by Ad-WWOX infection suppressed tumorigenicity of xenografts in nude mice, and intratumoral AZA treatment halted tumor growth. The data are consistent with a role for WWOX as a prostate cancer tumor suppressor and suggest that WWOX signal pathways should be further investigated in normal and cancerous prostate cells and tissues.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. qin.17@osu.edu
authors.forename: Haiyan R
authors.initials: HR
authors.lastname: Qin
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: Shuho
authors.initials: S
authors.lastname: Semba
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.forename: Teresa
authors.initials: T
authors.lastname: Druck
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Carl D
authors.initials: CD
authors.lastname: Morrison
authors.forename: Russell D
authors.initials: RD
authors.lastname: Klein
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010088:Oxidoreductases / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human