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.
Highlights
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide [1]
Cks1 is overexpressed in human HCC Cks1 overexpression occurs in various cancers, including oral squamous cell, lung, and gastric carcinomas
These results indicate that Cks1 overexpression may be associated with hepatocarcinogenesis
Summary
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide [1]. Despite the clinical significance of HCC, we only know the elemental basics of the molecular, cellular, and environmental mechanisms that drive disease pathogenesis, and only limited therapeutic options are available, of which many have negligible clinical benefits [3]. Elucidation of the predominant molecular events underlying hepatocarcinogenesis may help identify new therapeutic targets. Cks proteins were originally identified as subunits that interact closely with cyclin–cyclin-dependent kinase (CDK) complexes [4, 5]. Mammalian Cks (CDC28 protein kinase regulatory subunit 1B), located on chromosome 1q21.2, Authors' Affiliations: 1New Biologics Team, Mogam Biotechnology Research Institute, Yongin, Kyonggi-do; 2Laboratory of Biophysics, School of Biological Sciences, Seoul National University, Seoul; and 3Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Republic of Korea
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