title: KIF3a promotes proliferation and invasion via Wnt signaling in advanced prostate cancer.
abstract: Aberrant activation of the Wnt/β-catenin signaling pathway is a critical event in advanced prostate cancer, but the genetic alterations that activate the Wnt signaling pathway in many other cancers are rarely observed in prostate cancer. Other molecular mechanisms that regulate the Wnt signaling pathway in prostate cancer remain to be identified. Here, it is demonstrated that KIF3a, a subunit of kinesin-II motor protein, functions as an agonist of the Wnt signaling pathway in prostate cancer. KIF3a is upregulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3a correlate with a higher Gleason score, tumor-node-metastasis stage, and metastatic status of prostate cancer. Moreover, exogenous expression of KIF3a promoted cell growth in the benign prostate cells, whereas silencing KIF3a in cancer cells decreased cell proliferation, anchorage-independent cell growth, and cell migration/invasion. Mechanistically, KIF3a increases CK1-dependent DVL2 phosphorylation and β-catenin activation in prostate cancer cells, leading to transactivation of the Wnt-signaling target genes such as cyclin D1, HEF1, and MMP9. These findings support the notion that upregulation of KIF3a is causal of aberrant activation of Wnt signaling in advanced prostate cancer through the KIF3a-DVL2-β-catenin axis.
  
  
  CONCLUSIONS
  Inactivation of KIF3a may improve survival of patients with advanced prostate cancer in which Wnt signaling is activated.
authors.affiliation: Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, LCRC building Room 904, 1700 Tulane Avenue, New Orleans, LA 70112. wliu2@lsuhsc.edu.
authors.forename: Zun
authors.initials: Z
authors.lastname: Liu
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Rebowe
authors.forename: Zemin
authors.initials: Z
authors.lastname: Wang
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.forename: Zehua
authors.initials: Z
authors.lastname: Wang
authors.forename: John S
authors.initials: JS
authors.lastname: DePaolo
authors.forename: Jianhui
authors.initials: J
authors.lastname: Guo
authors.forename: Chiping
authors.initials: C
authors.lastname: Qian
authors.forename: Wanguo
authors.initials: W
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis; D018450:Disease Progression; D000072261:Dishevelled Proteins; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D046888:Tissue Array Analysis; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C087415:KIF3A protein, human; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D016547:Kinesins