title: Cell-cycle regulator Cks1 promotes hepatocellular carcinoma by supporting NF-κB-dependent expression of interleukin-8.
abstract: The cell-cycle regulator Cks1 has recently been implicated in Skp2-mediated ubiquitination of the tumor suppressor protein p27. In this article, we report that Cks1 exerts a Skp2-independent regulation of NF-κB that promotes interleukin-8 (IL-8) expression, which is critical to hepatocellular carcinoma (HCC) growth. Cks1 was upregulated frequently in human HCC tissues and cell lines. Cks1 knockdown in HCC cells elevated p27 levels and decreased tumorigenicity in a manner that was also associated with a strong downregulation of IL-8 expression. IL-8 downregulation was not phenocopied by either RNAi-mediated knockdown of Skp2 or ectopic overexpression of p27. However, attenuation of IL-8 expression itself was sufficient to blunt HCC growth. Mechanistic investigations revealed that IL-8 was controlled at a transcriptional level by Cks1 targeting of the NF-κB regulator IκBα, which led to NF-κB activation and IL-8 expression, through a p27-independent regulation of IκB kinase complex components. Collectively, our findings support the hypothesis that Cks1 supports hepatocarcinogenesis by NF-κB-mediated regulation of IL-8 expression, broadening the function of Cks1 in cancer beyond its role as a Skp2 cofactor in p27 ubiquitination.
authors.affiliation: New Biologics Team, Mogam Biotechnology Research Institute, Yongin, Kyonggi-do, Republic of Korea.
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Lee
authors.forename: Dae-Ghon
authors.initials: DG
authors.lastname: Kim
authors.forename: Jang-Seong
authors.initials: JS
authors.lastname: Kim
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
mesh_terms: D000818:Animals; D042846:CDC2-CDC28 Kinases; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000502:physiology*; D045744:Cell Line, Tumor / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D014410:Tumor Stem Cell Assay
chemical_list: C093090:CKS1B protein, human; D002352:Carrier Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; C000606205:Nfkbia protein, mouse; D044786:S-Phase Kinase-Associated Proteins; D000072000:NF-KappaB Inhibitor alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051550:I-kappa B Kinase; D042846:CDC2-CDC28 Kinases; D018844:Cyclin-Dependent Kinases