Abstract
This study investigated kinesin family member 7 (KIF7) expression and function in prostate cancer (PCa). Our results showed that KIF7 was significantly downregulated in PCa, compared with normal, benign prostatic hyperplasia and prostate intraepithelial neoplasia tissues, partially through promoter hypermethylation. We further investigated the effects of KIF7 coiled coil (CC) domain and motor domain (MD) on PCa development in vitro and in vivo. Our results showed that KIF7-CC but not KIF7-MD significantly attenuated proliferation and colony formation, impeded migration and invasion, induced apoptosis and sensitized PCa cells to paclitaxel. Further analysis revealed that KIF7-CC enhanced LKB1 expression and phosphorylation at Ser428, which induced PTEN phosphorylation at Ser380/Thr382/383 and consequently blocked AKT phosphorylation at Ser473. Downregulation of LKB1 significantly attenuated the suppressive effects of KIF7-CC on cell proliferation, colony formation and AKT phosphorylation. Furthermore, our in vivo studies showed that KIF7-CC reduced prostate tumorigenesis in cell-derived xenografts. Downregulation of LKB1 abrogated the anti-tumor effects of KIF7-CC in these xenografts. Taken together, these findings provide the first evidence to support the role of KIF7 as a negative regulator that inhibits PCa development partially through LKB1-mediated AKT inhibition.
Highlights
Prostate cancer (PCa) is the most common cancer in men and is the second leading cause of cancer death worldwide [1, 2]
These data showed that kinesin family member 7 (KIF7) but not KIF27 might play a suppressive role in prostate cancer (PCa)
We showed for the first time that KIF7-coiled coil (CC) but not KIF7MD acted as a tumor suppressor in PCa
Summary
Prostate cancer (PCa) is the most common cancer in men and is the second leading cause of cancer death worldwide [1, 2]. In 2015, 220,800 new cases of prostate cancer are found accounting for about one-quarter of new diagnoses in the United State. This means one of seven men is being diagnosed with prostate cancer over their lifetime. Androgen deprivation therapy tends to be the first-line treatment, most patients inevitably develop castration-resistant PCa 14-20 months after castration [3]. Resistance to taxane treatments severely limits the potential of these agents to improve the lives of patients [5]. A better understanding of the molecular mechanisms of PCa progression will develop more effective targets for diagnosis and enhance therapeutic responses to taxane-based therapy
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