CKS1B Human

What is CKS1B and what is its primary function in normal cells?

CKS1B is a member of the conserved cyclin kinase subunit 1 (CKS1) protein family that plays an essential role in cell cycle regulation. The protein is encoded by the CKS1B gene located on human chromosome 1q21.3 and consists of 79 amino acids with a molecular weight of approximately 9 kDa . In normal cells, CKS1B regulates the eukaryotic mitotic cycle by binding to and modulating the functions of cyclin-dependent protein kinase catalytic subunits . This interaction is crucial for normal cell division and growth as CKS1B helps coordinate the transition from G1 to S phase of the cell cycle .

The CKS1B protein serves as an indispensable regulatory unit of the SCFskp complex, which is involved in the ubiquitin-mediated degradation of cell cycle inhibitors, particularly p27kip1 . This function is critical for proper cell cycle progression, as p27kip1 is a member of the CIP/kip family that inhibits most CDKs and can arrest the cell cycle in S phase .

In which human cancers is CKS1B overexpression commonly observed?

CKS1B overexpression has been documented across numerous cancer types, demonstrating its pan-cancer significance. According to comprehensive analyses using databases like GENT2, CKS1B expression levels are significantly elevated in:

• Brain cancer

• Colon and colorectal cancer

• Bone cancer

• Ovarian cancer

• Pancreatic cancer

• Liver cancer (hepatocellular carcinoma)

• Lung cancer (both adenocarcinoma and squamous cell carcinoma)

• Breast invasive carcinoma

• Oral squamous cell carcinoma

• Retinoblastoma

• Multiple myeloma

• Leukemia

This widespread upregulation across diverse cancer types suggests that CKS1B dysregulation may represent a common oncogenic mechanism rather than a cancer-specific alteration . In multiple myeloma specifically, CKS1B has been identified as one of 70 high-risk genes whose expression is inversely proportional to patient survival in newly diagnosed cases .

How does CKS1B amplification affect clinical outcomes in cancer patients?

CKS1B amplification serves as an independent predictor of poor outcomes in various cancer types. In multiple myeloma, interphase fluorescence in-situ hybridization studies have revealed that CKS1B expression strongly correlates with DNA copy number (P<0.0001) . When validated in a cohort of 224 patients, CKS1B gene amplification was found to confer poor prognosis (P<0.0001) and remained an independent predictor of outcome in multivariate analyses (P=0.002) .

Amplification appears to be the most prevalent alteration type in lung cancer subtypes, with the highest frequency of 14.78% observed in 230 cases from the LUAD TCGA dataset . These findings collectively suggest that CKS1B amplification contributes to disease aggressiveness and treatment resistance.

What is the relationship between CKS1B and p27Kip1 in cancer cells?

CKS1B and p27Kip1 exhibit an inverse correlation in cancer cells, reflecting their functional relationship in cell cycle regulation. Studies have established that CKS1B mRNA and protein expression levels are inversely correlated with p27Kip1 protein levels . This relationship stems from CKS1B's role in the SCFSkp2 ubiquitin ligase complex, which targets p27Kip1 for degradation.

The mechanism involves CKS1B binding to Skp2, enhancing the interaction between Skp2 and phosphorylated p27Kip1, which marks p27Kip1 for ubiquitination and subsequent proteasomal degradation . This process reduces p27Kip1 levels, removing its inhibitory effect on cyclin-dependent kinases and thereby promoting cell cycle progression from G1 to S phase.

Experimental evidence supporting this relationship comes from RNA interference studies. When CKS1B mRNA is knocked down in myeloma cell lines, researchers observe:

• Reduced CKS1B mRNA and protein levels

• Accumulation of p27Kip1 protein

• Profound growth inhibition

These findings suggest that CKS1B may be the rate-limiting component of the SCFSkp2 complex in myeloma cells and potentially other cancer types, making it a promising therapeutic target.

What mechanisms contribute to CKS1B dysregulation in cancer?

CKS1B dysregulation in cancer occurs through multiple mechanisms that can vary across cancer types. Understanding these mechanisms is crucial for developing targeted therapeutic approaches:

• Gene Amplification: The most common mechanism of CKS1B overexpression is gene amplification, particularly at chromosome 1q21.3 . In multiple myeloma, CKS1B expression strongly correlates with DNA copy number . In lung adenocarcinoma, amplification frequency reaches 14.78% in some datasets .

• Epigenetic Regulation: DNA methylation analysis shows a negative correlation between CKS1B expression and methylation of certain CpG islands in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) . This suggests that hypomethylation of the CKS1B promoter contributes to its overexpression in these cancers.

• MicroRNA Regulation: Several miRNAs have been identified that target CKS1B, including miR-1258, miR-204, and miR-197. These miRNAs are often downregulated in cancer, leading to increased CKS1B expression. For example, miR-1258 has been shown to inhibit both mRNA and protein expression of CKS1B in colorectal cancer cells, exerting a tumor-suppressive effect . Similarly, miR-204 negatively regulates CKS1B expression in gastric cancer .

• Somatic Mutations: Mutations in the CKS1B gene have been identified in various cancers, although they appear less common than amplification. In lung cancer, missense and nonsense mutations have been identified in the CKS domain of the CKS1B protein .

These diverse mechanisms suggest that therapeutic strategies targeting CKS1B may need to be tailored based on the specific dysregulation mechanism present in each cancer type or individual patient.

How does CKS1B contribute to immune infiltration in the tumor microenvironment?

CKS1B expression significantly influences immune cell infiltration in the tumor microenvironment, with patterns that vary across cancer types. Pan-cancer analysis reveals that CKS1B expression correlates with:

• Cancer-Associated Fibroblasts (CAFs): CKS1B expression is closely related to CAF infiltration in several cancer types, including:

  • Breast invasive carcinoma

  • Kidney chromophobe

  • Lung adenocarcinoma

• Tumor-Infiltrating Lymphocytes (TILs): CKS1B expression correlates with TIL presence in:

  • Glioblastoma multiforme

  • Bladder urothelial carcinoma

  • Brain lower grade glioma

These correlations suggest that CKS1B may influence the composition of the tumor microenvironment, potentially affecting anti-tumor immune responses. The mechanism by which CKS1B impacts immune infiltration requires further investigation but may involve modulation of cytokine production, chemokine signaling, or direct effects on immune cell function.

The relationship between CKS1B and immune infiltration has important implications for immunotherapy approaches. Higher CKS1B expression might predict altered responses to immune checkpoint inhibitors or other immunotherapies, though additional studies are needed to establish this connection conclusively.

What molecular pathways are involved in CKS1B-mediated oncogenesis?

CKS1B contributes to oncogenesis through multiple molecular pathways and mechanisms, making it a versatile oncogenic factor:

• Cell Cycle Regulation: The primary mechanism involves CKS1B as a component of the SCFSkp2 ubiquitin ligase complex that targets p27Kip1 for degradation. By reducing p27Kip1 levels, CKS1B promotes cell cycle progression from G1 to S phase, leading to enhanced cellular proliferation .

• PI3K-Akt Signaling Pathway: Functional analyses have identified the PI3K-Akt signaling pathway as being involved in the mechanism of CKS1B-mediated oncogenesis . This pathway plays a critical role in cellular proliferation, survival, and metabolism.

• Kinase Activity Regulation: CKS1B influences kinase activity regulation, particularly through its interactions with cyclin-dependent kinases, which are central to cell cycle control .

• Co-expression Network: Analysis of the co-expression profile of CKS1B with other genes in lung cancer revealed strong correlation (R = 1.00) with Src homology 2 domain-containing transforming protein C1 (SHC1) . This suggests potential cooperative effects between CKS1B and other oncogenic factors.

Understanding these pathways provides potential points of intervention for therapeutic strategies targeting CKS1B-driven cancers. For example, inhibitors of the PI3K-Akt pathway could potentially synergize with approaches that directly target CKS1B.

What experimental approaches can effectively target CKS1B for cancer therapy?

Several experimental approaches show promise for targeting CKS1B in cancer therapy:

• RNA Interference: siRNA or shRNA targeting CKS1B has demonstrated effectiveness in preclinical models. In myeloma cell lines, RNA interference of CKS1B mRNA resulted in reduced CKS1B expression, accumulation of p27Kip1, and profound growth inhibition . This approach directly addresses CKS1B overexpression regardless of the underlying mechanism.

• miRNA-Based Therapies: Restoration of miRNAs that naturally target CKS1B, such as miR-1258, miR-204, or miR-197, represents another strategy. These miRNAs are often downregulated in cancer, and their restoration could normalize CKS1B expression. For instance, miR-1258 mimics have been shown to inhibit CKS1B expression in colorectal cancer cells .

• Small Molecule Inhibitors: Developing small molecules that disrupt the interaction between CKS1B and the SCFSkp2 complex or between CKS1B and its CDK binding partners could prevent CKS1B-mediated p27Kip1 degradation.

• Combination Therapies: Given CKS1B's role in drug resistance, combining CKS1B inhibition with conventional chemotherapies could potentially overcome resistance mechanisms and enhance treatment efficacy .

• Targeting Downstream Pathways: Inhibitors of pathways influenced by CKS1B, such as the PI3K-Akt pathway, could be effective in cancers with CKS1B overexpression .

The optimal approach may depend on cancer type, specific molecular alterations, and individual patient characteristics. Personalized strategies based on CKS1B expression levels, amplification status, or mutation profile may yield the best outcomes.

How can CKS1B expression be accurately measured in patient samples for clinical application?

Accurate measurement of CKS1B expression in patient samples is critical for its application as a biomarker. Several complementary methods are recommended:

• Fluorescence In-Situ Hybridization (FISH): FISH has proven effective for detecting CKS1B gene amplification. In multiple myeloma studies, interphase FISH revealed strong correlation between CKS1B expression and DNA copy number . This method is particularly useful for detecting chromosomal abnormalities at 1q21 where CKS1B is located.

• Quantitative Real-Time PCR (qRT-PCR): qRT-PCR provides sensitive measurement of CKS1B mRNA expression and can be performed on small tissue samples or even liquid biopsies. This technique has been validated in various cancer studies .

• RNA Sequencing: RNA-seq offers comprehensive gene expression profiling and can place CKS1B expression in the context of broader transcriptomic changes. This approach was used in pan-cancer analyses to investigate CKS1B expression across 33 tumor types .

• Immunohistochemistry (IHC): IHC can detect CKS1B protein expression in tissue sections and allows for assessment of cellular localization. Nuclear expression of CKS1B has been identified as a poor prognostic factor in some cancers .

• Methylation Analysis: Given the relationship between CKS1B expression and promoter methylation, analysis of CpG island methylation can provide additional insights into the mechanism of CKS1B dysregulation .

For clinical applications, a combinatorial approach may provide the most comprehensive assessment. For example, FISH can detect gene amplification while IHC confirms protein overexpression. This multi-modal approach helps ensure accurate patient stratification for prognostic and therapeutic purposes.