Cell Cycle and Senescence KIF 3 a Promotes Proliferation and Invasion via Wnt Signaling in Advanced Prostate Cancer

Aberrant activation of the Wnt/b-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 b-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–b-catenin axis. Implications: Inactivation of KIF3a may improve survival of patients with advanced prostate cancer in whichWnt signaling is activated. Mol Cancer Res; 12(4); 491–503. 2014 AACR. Introduction Prostate cancer remains themost diagnosed cancer and the second leading cause of cancer-related death in men in the United States (1). Although the incidence and mortality of this cancer are decreasing, advanced or aggressive prostate cancer remains the major cause of prostate cancer–related death (1). Aggressive prostate cancer is characterized by early age onset, high Gleason score (7–10), high prostate-specific antigen level (more than 50 ng/mL), and/or androgen independence (2, 3). The mortality of patients with aggressive prostate cancer is about four times higher than nonaggressive prostate cancer (4). Because aggressive and nonaggressive prostate cancer have dramatically different clinical outcomes, markers associated with aggressiveness of prostate cancer would be of great clinical utility. Identifying these markers and understanding their mechanisms will identify novel therapeutic or chemopreventive targets for patients with aggressive prostate cancer. Wnt signaling plays a crucial role in the progression of prostate cancer, and particularly, in aggressive prostate cancer (5–11). Wnt activation in other tumor types, such as colon cancer, is induced by gene mutations in APC, b-catenin, or AXIN1/2, components of the b-catenin destruction complex of the Wnt signaling pathway (12– 14). In cells harboring these mutations, b-catenin accumulates, translocates to the nucleus, and interacts with the Tcell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to activate specific Wnt target genes, such as c-Myc, cyclin D1, HEF1, and MMPs (matrix metalloproteinases) leading to tumorigenesis (15–18). In addition, increased phosphorylation of DVL2 also activates Wnt/b-catenin signaling in certain cancers (19). However, in contrast with colon cancer, mutations in b-catenin and APC are rare in prostate cancer (20). Only 5% of prostate tumors harbor activating mutations in b-catenin and even less contain APC mutations; however, the frequency of nuclear accumulation of b-catenin was reported in 23% to 83% of prostate cancer (21). Thus, the mechanisms activating the Wnt/b-catenin signaling pathway in a large proportion of prostate cancer have yet to be identified. KIF3a is amember of the kinesin family ofmotor proteins. It has been implicated downstream of the Hedgehog-signaling complex and has been shown to regulate early development, ciliogenesis, and tumorigenesis (22). Interestingly, Authors' Affiliation: Department of Genetics, Stanley S. Scott Cancer Center, Louisiana State University School of Medicine, New Orleans, Louisiana Z. Liu and R.E. Rebowe contributed equally to this work. Corresponding Author: Wanguo Liu, 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. Phone: 504-210-3326; Fax: 504-210-2970; E-mail: wliu2@lsuhsc.edu doi: 10.1158/1541-7786.MCR-13-0418 2014 American Association for Cancer Research. Molecular Cancer Research www.aacrjournals. org 491 on November 6, 2017. © 2014 American Association for Cancer Research. mcr.aacrjournals. org Downloaded from Published OnlineFirst January 10, 2014; DOI: 10.1158/1541-7786.MCR-13-0418