title: WWOX suppresses prostate cancer cell progression through cyclin D1-mediated cell cycle arrest in the G1 phase.
abstract: WW domain-containing oxidoreductase (WWOX) has been reported to be a tumor suppressor in multiple cancers, including prostate cancer. WWOX can induce apoptotic responses to inhibit tumor progression, and the other mechanisms of WWOX in tumor suppression have also been reported recently. In this study, we found significant down-regulation of WWOX in prostate cancer specimens and prostate cancer cell lines compared with the normal controls. In addition, an ectopically increased WWOX expression repressed tumor progression both in vitro and in vivo. Interestingly, overexpression of WWOX in 22Rv1 cells led to cell cycle arrest in the G1 phase but did not affect sub-G1 in flow cytometry. GFP-WWOX overexpressed 22Rv1 cells were shown to inhibit cell cycle progression into mitosis under nocodazole treatment in flow cytometry, immunoblotting and GFP fluorescence. Further, cyclin D1 but not apoptosis correlated genes were down-regulated by WWOX both in vitro and in vivo. Restoration of cyclin D1 in the WWOX-overexpressed 22Rv1 cells could abolish the WWOX-mediated tumor repression. In addition, WWOX impair c-Jun-mediated cyclin D1 promoter activity. These results suggest that WWOX inhibits prostate cancer progression through negatively regulating cyclin D1 in cell cycle lead to G1 arrest. In summary, our data reveal a novel mechanism of WWOX in tumor suppression.
authors: a Institute of Clinical Medicine; Medical College ; National Cheng Kung University ; Tainan , Taiwan.
authors: Jen-Tai
authors: JT
authors: Lin
authors: Hao-Yi
authors: HY
authors: Li
authors: Nan-Shan
authors: NS
authors: Chang
authors: Cheng-Han
authors: CH
authors: Lin
authors: Yu-Chia
authors: YC
authors: Chen
authors: Pei-Jung
authors: PJ
authors: Lu
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D018450:Disease Progression; D016193:G1 Phase; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008819:Mice, Nude; D010088:Oxidoreductases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: C530104:CCND1 protein, human; D016755:Proto-Oncogene Proteins c-jun; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human
keywords: ATCC, American Type Culture Collection; CCND1, cyclin D1; GFP, Green fluorescent protein; RT-PCR, Reverse transcription polymerase chain reaction; WWOX; WWOX, WW domain-containing oxidoreductase; cell cycle; cyclin D1; prostate cancer; rEGF, Recombinant Epidermal Growth Factor; tumor suppressor