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-kB 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-kB regulator IkBa, which led to NF-kB activation and IL-8 expression, through a p27-independent regulation of IkB kinase complex components. Collectively, our findings support the hypothesis that Cks1 supports hepatocarcinogenesis by NF-kB-mediated regulation of IL-8 expression, broadening the function of Cks1 in cancer beyond its role as a Skp2 cofactor in p27 ubiquitination. Cancer Res; 71(21); 6827-35. Ó2011 AACR.

NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma

“…CKS1B is an essential protein for normal cell division and growth (6), and is expressed at a high level in various cancer tissues including hepatocellular carcinoma (7), colon (8), lung (9), oral squamous cell carcinoma (10), breast cancer (11), and others. In MM, amplification of region 1q21, which includes the CKS1B gene, identifies a subpopulation with poor prognosis, an aggressive clinical course, and few therapeutic options (12, 13).…”

Cks1 Enhances Transcription Efficiency at the GAL1 Locus by Linking the Paf1 Complex to the 19S Proteasome

“…Moreover, in some ductal breast carcinomas, the expression of Cdk1, cyclin B1, and cyclin A2, as well as Cks proteins, is coordinately upregulated (54). However, although Cks protein overexpression is a characteristic of many forms of cancer (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73) and Cks1 deletion has protective effects in some mouse cancer models and cell line studies (74)(75)(76), it is not clear that Cks-mediated oncogenicity is related to transcriptional functions. As Cks1 is a component of the SCF Skp2 ubiquitin ligase, it has been suggested that oncogenic functions of Cks1 might be mediated by affecting the stability of the Cdk inhibitor p27 Kip1 , an SCF Skp2 target (77).…”

Cks1 proteasomal degradation is induced by inhibiting Hsp90-mediated chaperoning in cancer cells

“…Increased Cks1 expression is strongly correlated to tumor aggressiveness in different tumors of gastrointestinal system such as esophagus [33], stomach [34,35], colon [5,36,37], and liver [14,38]. However, whether the aberrantly high Cks1 protein found in gastrointestinal tumors can be reduced by inhibiting Hsp90 function has not been examined.…”

“…In fact, inhibition of Hsp90 in colorectal cancer downregulates NF-κB, leading to inhibition of epithelial mesenchymal transition, motility, and invasiveness [40]. Interestingly, Cks1 supports hepatocarcinogenesis through regulation of NF-κB pathway [14]. Collectively, these studies suggest the notion that part of the decrease in tumorigenic properties of colorectal cancer cells following Hsp90 inhibition may occur through potential Cks1-dependent mechanism.…”

“…Similarly, tumorigenesis is also abrogated by knockout of Cks1 in a cyclin E-induced mammary carcinoma model [12]. RNAi strategies of Cks1 inhibition using either siRNA duplexes or shRNA vectors have also been successful in vitro and have demonstrated inhibition of cancer cell proliferation and cell cycle blockade in several instances [9,14,15]. However, depletion of Cks1 gene expression by such means has not been demonstrated to be a feasible therapeutic strategy, either in animal models or in the clinic.…”