title: The tumor suppressor pVHL down-regulates never-in-mitosis A-related kinase 8 via hypoxia-inducible factors to maintain cilia in human renal cancer cells.
abstract: NEK8 (never in mitosis gene A (NIMA)-related kinase 8) is involved in cytoskeleton, cilia, and DNA damage response/repair. Abnormal expression and/or dysfunction of NEK8 are related to cancer development and progression. However, the mechanisms that regulate NEK8 are not well declared. We demonstrated here that pVHL may be involved in regulating NEK8. We found that CAK-I cells with wild-type vhl expressed a lower level of NEK8 than the cells loss of vhl, such as 786-O, 769-P, and A-498 cells. Moreover, pVHL overexpression down-regulated the NEK8 protein in 786-O cells, whereas pVHL knockdown up-regulated NEK8 in CAK-I cells. In addition, we found that the positive hypoxia response elements (HREs) are located in the promoter of the nek8 sequence and hypoxia could induce nek8 expression in different cell types. Consistent with this, down-regulation of hypoxia-inducible factors α (HIF-1α or HIF-2α) by isoform-specific siRNA reduced the ability of hypoxia inducing nek8 expression. In vivo, NEK8 and HIF-1α expression were increased in kidneys of rats subjected to an experimental hypoxia model of ischemia and reperfusion. Furthermore, NEK8 siRNA transfection significantly blocked pVHL-knockdown-induced cilia disassembling, through impairing the pVHL-knockdown-up-regulated NEK8 expression. These results support that nek8 may be a novel hypoxia-inducible gene. In conclusion, our findings show that nek8 may be a new HIF target gene and pVHL can down-regulate NEK8 via HIFs to maintain the primary cilia structure in human renal cancer cells.
authors.affiliation: From the School of Medicine.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Ding
authors.affiliation: From the School of Medicine, the Institute of Tumor, and.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the School of Medicine.
authors.forename: Qiong-Ying
authors.initials: QY
authors.lastname: Hu
authors.affiliation: the Taizhou Municipal Hospital, Taizhou, Zhejiang, 318000 China.
authors.forename: Shuang-Chun
authors.initials: SC
authors.lastname: Liu
authors.affiliation: From the School of Medicine, the Institute of Tumor, and the School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou, Zhejiang 318000 and 9220229@qq.com.
authors.forename: Guang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002923:Cilia / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007668:Kidney / Q000201:enzymology; D007680:Kidney Neoplasms / Q000378:metabolism; D008297:Male; D000072379:NIMA-Related Kinases; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury; D014162:Transfection; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D011494:Protein Kinases; C458529:NEK8 protein, human; D000072379:NIMA-Related Kinases; C577692:Nek8 protein, rat; D017346:Protein Serine-Threonine Kinases; C497446:VHL protein, human
keywords: Cancer Biology; Cell Signaling; Cilia; Hypoxia; Hypoxia-inducible Factor (HIF); NEK8; Renal Carcinoma; pVHL