Gene Summary

Gene:CKS1B; CDC28 protein kinase regulatory subunit 1B
Aliases: CKS1, ckshs1, PNAS-16, PNAS-18
Summary:CKS1B protein binds to the catalytic subunit of the cyclin dependent kinases and is essential for their biological function. The CKS1B mRNA is found to be expressed in different patterns through the cell cycle in HeLa cells, which reflects a specialized role for the encoded protein. At least two transcript variants have been identified for this gene, and it appears that only one of them encodes a protein. [provided by RefSeq, Sep 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinases regulatory subunit 1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CKS1B (cancer-related)

Meyer SE, Muench DE, Rogers AM, et al.
miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.
J Exp Med. 2018; 215(8):2115-2136 [PubMed] Free Access to Full Article Related Publications
We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found

Walker BA, Mavrommatis K, Wardell CP, et al.
A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis.
Leukemia. 2019; 33(1):159-170 [PubMed] Free Access to Full Article Related Publications
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R

Ashok V, Ranganathan R, Chander S, et al.
Comparison of Diagnostic Yield of a FISH Panel Against Conventional Cytogenetic Studies for Hematological Malignancies: A South Indian Referral Laboratory Analysis Of 201 Cases
Asian Pac J Cancer Prev. 2017; 18(12):3457-3464 [PubMed] Free Access to Full Article Related Publications
Objectives: Genetic markers are crucial fort diagnostic and prognostic investigation of hematological malignancies (HM). The conventional cytogenetic study (CCS) has been the gold standard for more than five decades. However, FISH (Fluorescence in Situ Hybridization) testing has become a popular modality owing to its targeted approach and the ability to detect abnormalities in non-mitotic cells. We here aimed to compare the diagnostic yields of a FISH panel against CCS in HMs. Methods: Samples of bone marrow and peripheral blood for a total of 201 HMs were tested for specific gene rearrangements using multi-target FISH and the results were compared with those from CCS. Results: Exhibited a greater diagnostic yield with a positive result in 39.8% of the cases, as compared to 17.9% of cases detected by CCS. Cases of chronic lymphocytic leukaemia (CLL) benefited the most by FISH testing, which identified chromosomal aberrations beyond the capacity of CCS. FISH was least beneficial in myelodysplastic syndrome (MDS) where the highest concordance with CCS was exhibited. Acute lymphocytic leukaemia (ALL) demonstrated greater benefit with CCS. In addition, we found the following abnormalities to be most prevalent in HMs by FISH panel testing: RUNX1 (21q22) amplification in ALL, deletion of D13S319/LAMP1 (13q14) in CLL, CKS1B (1q21) amplification in multiple myeloma and deletion of EGR1/RPS14 (5q31/5q32) in MDS, consistent with the literature. Conclusions: In conclusion, FISH was found to be advantageous in only a subset of HMs and cannot completely replace CCS. Utilization of the two modalities in conjunction or independently should depend on the indicated HM for an optimal approach to detecting chromosomal aberrations.

Shrestha S, Yang CD, Hong HC, et al.
Integrated MicroRNA-mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in Gastric Cancer by Targeting CKS1B, CXCL1 and GPRC5A.
Int J Mol Sci. 2017; 19(1) [PubMed] Free Access to Full Article Related Publications
Gastric cancer (GC) is the second most frequent cause of cancer-related deaths worldwide. MicroRNAs are single-stranded RNA molecules of 21-23 nucleotides that regulate target gene expression through specific base-pairing interactions between miRNA and untranslated regions of targeted mRNAs. In this study, we generated a multistep approach for the integrated analysis of miRNA and mRNA expression. First, both miRNA and mRNA expression profiling datasets in gastric cancer from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) identified 79 and 1042 differentially expressed miRNAs and mRNAs, respectively, in gastric cancer. Second, inverse correlations between miRNA and mRNA expression levels identified 3206 miRNA-mRNA pairs combined with 79 dysregulated miRNAs and their 774 target mRNAs predicted by three prediction tools, miRanda, PITA, and RNAhybrid. Additionally, miR-204, which was found to be down-regulated in gastric cancer, was ectopically over-expressed in the AGS gastric cancer cell line and all down-regulated targets were identified by RNA sequencing (RNA-seq) analysis. Over-expression of miR-204 reduced the gastric cancer cell proliferation and suppressed the expression of three targets which were validated by qRT-PCR and luciferase assays. For the first time, we identified that

El Naofal M, Kim A, Yon HY, et al.
Role of CDKN2C Fluorescence In Situ Hybridization in the Management of Medullary Thyroid Carcinoma.
Ann Clin Lab Sci. 2017; 47(5):523-528 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC), an aggressive form of thyroid cancer, occurs sporadically in approximately 75% of MTCs.

Grey W, Ivey A, Milne TA, et al.
The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(1):105-116 [PubMed] Free Access to Full Article Related Publications
The Cdc28 protein kinase subunits, Cks1 and Cks2, play dual roles in Cdk-substrate specificity and Cdk-independent protein degradation, in concert with the E3 ubiquitin ligase complexes SCF

Hao S, Lin P, Medeiros LJ, et al.
Clinical implications of cytogenetic heterogeneity in multiple myeloma patients with TP53 deletion.
Mod Pathol. 2017; 30(10):1378-1386 [PubMed] Free Access to Full Article Related Publications
TP53 deletion (ΔTP53) in myeloma is known to be a high-risk finding associated with poorer prognosis. The prognostic impact of underlying cytogenetic heterogeneity in patients with myeloma associated with ΔTP53 is unknown. We studied 90 patients with myeloma associated with ΔTP53 identified by interphase fluorescence in situ hybridization and assessed the impact of karyotype and coexisting alterations of IGH, RB1, and CKS1B. There were 54 men and 36 women with a median age of 59 years (range 38-84); 14 patients had a normal karyotype (NK/ΔTP53), 73 had a complex karyotype (CK/ΔTP53), and 3 had a non-complex abnormal karyotype. Patients with CK/ΔTP53 showed a significantly poorer overall survival compared with patients with NK/ΔTP53 (P=0.0243). Furthermore, in the CK/ΔTP53 group, patients with IGH rearrangement other than t(11;14)(q13;q32)/CCND1-IGH, designated as adverse-IGH, had an even worse outcome (P=0.0045). In contrast, RB1 deletion, CKS1B gain, ploidy, additional chromosome 17 abnormalities, or ΔTP53 clone size did not impact prognosis. Stem cell transplant did not improve overall survival in either the NK/ΔTP53 or CK/ΔTP53 (P=0.8810 and P=0.1006) groups, but tandem stem cell transplant did improve the overall survival of patients with CK/ΔTP53 (P=0.0067). Multivariate analysis confirmed in this cohort that complex karyotype (hazard ratio 1.976, 95% CI 1.022-3.821, P=0.043), adverse-IGH (hazard ratio 3.126, 95% CI 1.192-8.196, P=0.020), and tandem stem cell transplant independently correlate with overall survival (hazard ratio 0.281, 95% CI 0.091-0.866, P=0.027). We conclude that comprehensive genetic assessment adds to TP53 status in the risk stratification of myeloma patients.

Liu Y, Wang W, Li Y, et al.
CKS1BP7, a Pseudogene of CKS1B, is Co-Amplified with IGF1R in Breast Cancers.
Pathol Oncol Res. 2018; 24(2):223-229 [PubMed] Related Publications
Pseudogenes have been reported to exhibit functional roles. Amplification or overexpression of CDC28 protein kinase regulatory subunit 1B (CKS1B) was found in various human cancers. But it was known little about CKS1B pseudogene 7 (CKS1BP7), a pseudogene sharing considerable sequence identity with CKS1B. The aim of this study was to evaluate copy number alterations (CNAs) of CKS1BP7 and address its potential roles in breast cancer. We detected copy numbers of CKS1BP7 and insulin-like growth factor 1 receptor (IGF1R) using quantitative multi-gene fluorescence in situ hybridization (QM-FISH) technique, compared their status in both invasive carcinoma and ductal carcinoma in situ (DCIS) components within the same tumors, and investigated the associations of CNAs with tumor features and patients outcomes. Amplification of CKS1BP7 (dot-like pattern) was found in 28.8% of all cases, while amplified IGF1R (cluster pattern) was identified in 24.2% of all patients. The two events often co-existed (p = 0.01). Within the same tumors, identical CNAs of CKS1BP7 and IGF1R were found in DCIS and invasive carcinoma. Moreover, amplification of both genes was more frequent in aneuploidy tumors and the tumors with high ki67, but wasn't associated with patients' outcome. In summary, CKS1BP7 amplification is a frequent event in breast cancer and often co-occurs with amplified IGF1R, which provides evidence supporting the interactions between CKS1BP7 and IGF1R during mammary carcinogenesis. Our findings suggest that CKS1BP7 as well as IGF1R may serve as potential biomarkers for early detection and predict prognosis in breast cancer.

Malek E, Abdel-Malek MA, Jagannathan S, et al.
Pharmacogenomics and chemical library screens reveal a novel SCF
Leukemia. 2017; 31(3):645-653 [PubMed] Free Access to Full Article Related Publications
While clinical benefit of the proteasome inhibitor (PI) bortezomib (BTZ) for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin ligase Skp1-Cullin-1-Skp2 (SCF

Bock F, Lu G, Srour SA, et al.
Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation.
Biol Blood Marrow Transplant. 2016; 22(12):2159-2164 [PubMed] Free Access to Full Article Related Publications
The gain/amplification of the CKS1B gene on chromosome 1q21 region is associated with a poor outcome in patients with multiple myeloma (MM). However, there are limited data on the outcome of patients with CKS1B amplification after a single high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively evaluated the outcome of patients with CKS1B amplification who received an auto-HCT between June 2012 and July 2014 at our institution. We identified 58 patients with MM and CKS1B gene amplification detected by fluorescent in situ hybridization (FISH). We compared their outcomes with a propensity score-matched control group of 58 patients without CKS1B amplification who were treated at approximately the same time. The primary objective was to compare the progression-free (PFS) and overall survival (OS) between the CKS1B and the control groups. Stratified log-rank test with the matched pairs as strata and double robust estimation under the Cox model were used to assess the effect of CKS1B gene amplification on PFS or OS in the matched cohort. Patients in the CKS1B and control groups were well matched for age, gender, disease status, year of auto-HCT, response to pretransplantation therapy, and baseline hemoglobin level. In both groups, 57% patients were in first remission and 43% had relapsed disease at auto-HCT. Twenty-seven (47%) patients with CKS1B amplification had concurrent monosomy 13 or 13q deletion; 6 (10%) by conventional cytogenetics only, 16 (28%) by FISH only, and 5 (9%) by both. Median follow-up after auto-HCT was 25.4 months. The median PFS of the CKS1B and the control groups were 15.0 months and 33.0 months (P = .002), respectively. The median OS have not been reached yet. The 2-year OS rates in the CKS1B and the control groups were 62% and 91% (P = .02), respectively. In conclusion, Patients with CKS1B amplification are more likely to have additional high-risk cytogenetic abnormalities and a shorter PFS and OS after an auto-HCT.

Carreras J, Kikuti YY, Beà S, et al.
Clinicopathological characteristics and genomic profile of primary sinonasal tract diffuse large B cell lymphoma (DLBCL) reveals gain at 1q31 and RGS1 encoding protein; high RGS1 immunohistochemical expression associates with poor overall survival in DLBCL not otherwise specified (NOS).
Histopathology. 2017; 70(4):595-621 [PubMed] Related Publications
AIMS: We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B cell lymphoma (DLBCL
METHODS AND RESULTS: In the training set, 82% had a non-germinal center B-cell-like (Hans' Classifier) (non-GCB) phenotype and 18% were Epstein-Barr virus-encoded small RNAs (EBER)

Krishnan A, K D, Babu P S S, et al.
Oncogenic Actions of SKP2 Involves Deregulation of CDK1 Turnover Mediated by FOXM1.
J Cell Biochem. 2017; 118(4):797-807 [PubMed] Related Publications
Cyclin-dependent kinases (cdks) are central catalytic units of cell division cycle. Among the cdk family members, cdk1 has critical roles in multiple phases of the cell cycle. Aberrant expression or hyper-actions of cdk1 are tumorigenic and yet the complex oncogenic network that regulates its turnover is poorly understood. We found a hitherto unexplored functional connection between skp2 and cdk1 turn over. In vitro knockdown or overexpression of skp2 in cultured cells reduced or induced cdk1 expression indicating skp2 as a positive driver for cdk1. A partial inhibitory role for p27 was identified in this context. Interestingly, concurrent overexpression of skp2 and p27 favored cdk1 upregulation in vitro, which correlated well with similar observations in clinical tumor samples. We found that the transcription factor FOXM1 may play a central role in the skp2-cdk1 loop. Additional molecular involvement in the skp2-cdk1 loop was also explored. In conclusion, our results revealed hitherto unexplored p27 independent molecular mechanisms for skp2 driven tumor progression. Our results support the previous findings that skp2 may be a potential therapeutic target for the management of tumors. J. Cell. Biochem. 118: 797-807, 2017. © 2016 Wiley Periodicals, Inc.

Reid RJ, Du X, Sunjevaric I, et al.
A Synthetic Dosage Lethal Genetic Interaction Between CKS1B and PLK1 Is Conserved in Yeast and Human Cancer Cells.
Genetics. 2016; 204(2):807-819 [PubMed] Free Access to Full Article Related Publications
The CKS1B gene located on chromosome 1q21 is frequently amplified in breast, lung, and liver cancers. CKS1B codes for a conserved regulatory subunit of cyclin-CDK complexes that function at multiple stages of cell cycle progression. We used a high throughput screening protocol to mimic cancer-related overexpression in a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential only when CKS1 is overexpressed, a synthetic dosage lethal (SDL) interaction. Mutations in multiple genes affecting mitotic entry and mitotic exit are highly enriched in the set of SDL interactions. The interactions between Cks1 and the mitotic entry checkpoint genes require the inhibitory activity of Swe1 on the yeast cyclin-dependent kinase (CDK), Cdc28. In addition, the SDL interactions of overexpressed CKS1 with mutations in the mitotic exit network are suppressed by modulating expression of the CDK inhibitor Sic1. Mutation of the polo-like kinase Cdc5, which functions in both the mitotic entry and mitotic exit pathways, is lethal in combination with overexpressed CKS1 Therefore we investigated the effect of targeting the human Cdc5 ortholog, PLK1, in breast cancers with various expression levels of human CKS1B Growth inhibition by PLK1 knockdown correlates with increased CKS1B expression in published tumor cell data sets, and this correlation was confirmed using shRNAs against PLK1 in tumor cell lines. In addition, we overexpressed CKS1B in multiple cell lines and found increased sensitivity to PLK1 knockdown and PLK1 drug inhibition. Finally, combined inhibition of WEE1 and PLK1 results in less apoptosis than predicted based on an additive model of the individual inhibitors, showing an epistatic interaction and confirming a prediction of the yeast data. Thus, identification of a yeast SDL interaction uncovers conserved genetic interactions that can affect human cancer cell viability.

Hu M, Wang M, Lu H, et al.
Loss of miR-1258 contributes to carcinogenesis and progression of liver cancer through targeting CDC28 protein kinase regulatory subunit 1B.
Oncotarget. 2016; 7(28):43419-43431 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is the leading cause of cancer related death worldwide. The number of deaths is proportional to the global incidence, which highlights the aggressive tumor biology and lack of effective therapies. Dysregulation of microRNAs has been implicated in carcinogenesis and progression of liver cancer. Here, we identified that miR-1258 was significantly downregulated in HCC and associated with poor patients' survival. Overexpression of miR-1258 significantly inhibits liver cancer cell growth, proliferation and tumorigenicity through increasing cell cycle arrest in G0/G1 phase and promotes cell apoptosis. Interestingly, stable overexpression of miR-1258 suppresses cell migration, stemness and increases sensitivity of HCC cells to chemotherapy drug like doxorubicin. The CDC28 protein kinase regulatory subunit 1B (CKS1B) was identified as a functional downstream target of miR-1258. Re-expression of CKS1B overcomes miR-1258 induced apoptosis and increases stemness of HCC cells, suggesting that loss of miR-1258 contributes to carcinogenesis and progression of liver cancer through targeting CKS1B . Therefore, loss of miR-1258 may be a potential diagnostic and prognostic biomarker and blocking miR-1258-CKS1B axis is a potential therapeutic strategy in HCC.

Zhao H, Lu Z, Bauzon F, et al.
p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer.
Oncogene. 2017; 36(1):60-70 [PubMed] Free Access to Full Article Related Publications

Black JC, Zhang H, Kim J, et al.
Regulation of Transient Site-specific Copy Gain by MicroRNA.
J Biol Chem. 2016; 291(10):4862-71 [PubMed] Free Access to Full Article Related Publications
Intra-tumor copy number heterogeneity is commonly observed in cancer; however, the molecular mechanisms that contribute to heterogeneity remain poorly understood. Up-regulation of the histone demethylase KDM4A promotes transient site-specific copy gain (TSSG) in cells; therefore, uncovering how KDM4A levels are controlled is important for understanding the regulation of copy number heterogeneity. Here, we demonstrate that KDM4A is regulated by hsa-mir-23a-3p, hsa-mir-23b-3p, and hsa-mir-137. Altering expression of these microRNAs (miRNAs) regulates KDM4A-dependent TSSG. miRNA inhibition promoted copy gains and increased expression of the drug-resistant oncogene CKS1B, which was further substantiated in primary breast tumors. Consistent with increased CKS1B expression, miRNA inhibition reduced breast cancer cell sensitivity to cisplatin. Our data identify these miRNAs as regulators of TSSG and copy gains of a drug resistance gene.

Zheng J, Li Q, Wang W, et al.
Apoptosis-related protein-1 acts as a tumor suppressor in cholangiocarcinoma cells by inducing cell cycle arrest via downregulation of cyclin-dependent kinase subunits.
Oncol Rep. 2016; 35(2):809-16 [PubMed] Related Publications
Cholangiocarcinoma, a malignancy arising from the biliary tract, is associated with high mortality due to the late diagnosis and lack of effective therapeutic approaches. Our knowledge of the molecular alterations during the carcinogenesis of cholangiocarcinoma is limited. Previous study suggests that apoptosis-related protein-1 (Apr-1) is involved in cancer cell proliferation and survival. In the present study, we first detected the expression pattern of Apr-1 in human cholangiocarcinoma tissues and the effects of forced Apr-1 expression on cell proliferation and cell cycle progression. Cell cycle gene array analysis was used to identify downstream molecules that were regulated by Apr-1, and their expression levels were further evaluated in human cholangiocarcinoma tissues. We showed that Apr-1 expression was downregulated in human cholangiocarcinoma tissues. Forced expression of Apr-1 inhibited cell proliferation of cholangiocarcinoma cell line QBC939 and induced G2/M phase arrest. Downregulation of cell cycle-related genes cyclin-dependent kinase (Cdk) 2, and cyclin-dependent kinase subunits (Cks) 1 and 2 was involved in Apr-1-induced cell cycle arrest. Furthermore, we found that Cdk2 and Cks1/2 expression levels were elevated in human cholangiocarcinoma tissues. Taken together, our data showed that Apr-1 plays a crucial role in cell proliferation by controlling cell cycle progression, implying a tumor-suppressor function of Apr-1 in cholangiocarcinoma carcinogenesis. Thus, the present study provides a rationale to further study the underlying mechanisms of Apr-1 downregulation in cholangiocarcinoma for exploring potential diagnostic and therapeutic targets.

Lin L, Fang Z, Lin H, et al.
Depletion of Cks1 and Cks2 expression compromises cell proliferation and enhance chemotherapy-induced apoptosis in HepG2 cells.
Oncol Rep. 2016; 35(1):26-32 [PubMed] Free Access to Full Article Related Publications
The present study explored the oncogenic roles of overexpressed Cks1 and Cks2 in human hepatocellular carcinoma cells. Gene expression of Cks1 and Cks2 in HepG2 cells was disrupted by siRNA or increased by cDNA transfection. Cell proliferation was assayed by CCK-8 analysis and cell counting. Cisplatin-induced apoptosis after transfection was measured by flow cytometry using Annexin V/propidium iodide (PI) double staining. Cell cycle changes after transfection were determined by flow cytometry with PI staining. Protein levels of Akt and GSK-3β were measured after transfection. The results revealed that HepG2 proliferation was decreased by depletion of endogenous Cks1 or Cks2, and increased by overexpression of Cks1 or Cks2. HepG2 apoptosis increased concordantly with the decline of Cks1 or Cks2 expression. Overexpression of Cks1 or Cks2 prevented cell apoptosis. Protein levels of p‑Akt and p‑GSK-3β were downregulated after RNA interference of Cks1 or Cks2. In conclusion, Cks1 and Cks2 promoted proliferation and prevented apoptosis of HepG2 cells. The Akt/GSK-3β-related PI3K/Akt signaling pathway may be a key signaling pathway that is involved in the regulation of cell growth and cell death.

Huang J, Zhou Y, Thomas GS, et al.
NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma.
Clin Cancer Res. 2015; 21(24):5532-42 [PubMed] Free Access to Full Article Related Publications
PURPOSE: CKS1B is significantly upregulated in multiple myeloma and associated with poor prognosis. The identification of novel therapies is essential for effective treatment of patients resistant to chemotherapy. The NEDD8 inhibitor MLN4924 selectively targets SCF(Skp2) activation and offers a more specific approach to protein degradation inhibition than total proteasomal inhibition. The goal of this study was to evaluate whether MLN4924 is effective in high CKS1B conditions and identify mechanisms regulating drug potency.
EXPERIMENTAL DESIGN: Bortezomib and MLN4924 sensitivity was assessed through proliferation, viability, clonogenic potential, and senescence induction in cells overexpressing CKS1B. The mechanism for MLN4924 sensitivity was elucidated by immunoblot analysis of SCF(skp) substrates and confirmed by shRNA knockdown. The clinical relevance of the NEDD8 pathway was examined in gene expression profiles (GEP) derived from healthy people, patients with monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.
RESULTS: Cells overexpressing CKS1B were resistant to bortezomib but sensitive to MLN4924. Treatment of CKS1B-overexpressing cells with MLN4924 decreased proliferation, clonogenicity, and induced senescence. MLN4924, but not bortezomib, induced stabilization of p21 and knockdown of p21 resulted in loss of MLN4924 sensitivity. Patients with MGUS and multiple myeloma exhibited increased expression of NEDD8 pathway genes relative to normal plasma cells. Multiple myeloma patients with high NEDD8 expression were linked to bortezomib resistance in clinical trials, and had inferior outcomes.
CONCLUSIONS: Our data demonstrate that cells with elevated CKS1B expression are resistant to bortezomib but sensitive to MLN4924 and offer a mechanism through the stabilization of p21. These findings provide rationale for targeting the NEDD8 pathway in multiple myeloma patients exhibiting elevated expression of CKS1B. Clin Cancer Res; 21(24); 5532-42. ©2015 AACR.

Bochis OV, Irimie A, Pichler M, Berindan-Neagoe I
The role of Skp2 and its substrate CDKN1B (p27) in colorectal cancer.
J Gastrointestin Liver Dis. 2015; 24(2):225-34 [PubMed] Related Publications
Colorectal cancer is one of the most frequent cancers worldwide, having the fourth mortality rate among cancers in both sexes. Numerous studies are investigating the signalling pathways and different factors involved in the development and progression of colorectal cancer. It has recently been shown that the S-phase kinase-associated protein 2 (Skp2) overexpression plays an important role in the pathogenesis of colorectal cancer. We review the role of Skp2 and its ubiquitin-proteasome pathway in colorectal cancer. The F-box protein Skp2, a component of the SCF (Skp1-Cullin 1-F-box) E3 ubiquitin-ligase complex, has been shown to regulate cellular proliferation, cancer progression and metastasis by targeting several cell cycle regulators for ubiquitination and subsequent 26S proteasome degradation. The best known protein substrate of the Skp2 is the cyclin-dependent kinase inhibitor 1B (CDKN1B), also known as p27Kip1. Overexpression of Skp2 and loss of CDKN1B (p27) was strongly associated with aggressive tumor behavior and poor clinical outcome in a variety of cancers, including colorectal cancer. An efficient interaction between Skp2 and CDKN1B (p27) requires the presence of an essential activator of the SCF-Skp2 complex, the cyclin-dependent kinase subunit 1 (Cks1) cofactor. Alterations in the Skp2, Cks1 and CDKN1B (p27) expression have major effects on colorectal carcinogenesis and may serve as an important and independent prognostic marker. Furthermore, we highlight that Skp2 may be a promising therapeutic target for colorectal cancer, and development of Skp2 inhibitors would have a great impact on colorectal cancer therapy.

Sevcikova S, Paszekova H, Besse L, et al.
Extramedullary relapse of multiple myeloma defined as the highest risk group based on deregulated gene expression data.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015; 159(2):288-93 [PubMed] Related Publications
BACKGROUND: Multiple myeloma (MM) is characterized by malignant proliferation of plasma cells (PC) which accumulate in the bone marrow (BM). The advent of new drugs has changed the course of the disease from incurable to treatable, but most patients eventually relapse. One group of MM patients (10-15%) is considered high-risk because they relapse within 24 months. Recently, extramedullary relapse of MM (EM) has been observed more frequently. Due to its aggressivity and shorter survival, EM is also considered high-risk.
AIMS: The goal of this study was to determine if the so-called high-risk genes published by the University of Arkansas group (UAMS) are even more deregulated in EM patients than in high-risk MM patients and if these patients may be considered high-risk.
METHODS: Nine samples of bone marrow plasma cells from MM patients as well as 9 tumors and 9 bone marrow plasma cells from EM patients were used. Quantitative real-time PCR was used for evaluation of expression of 15 genes connected to the high-risk signature of MM patients.
RESULTS: Comparison of high-risk plasma cells vs extramedullary plasma cells revealed 4 significantly deregulated genes (CKS1B, CTBS, NADK, YWHAZ); moreover, comparison of extramedullary plasma cells vs extramedullary tumors revealed significant differences in 9 out of 15 genes. Of these, 6 showed significant changes as described by the UAMS group (ASPM, SLC19A1, NADK, TBRG4, TMPO and LARS2).
CONCLUSIONS: Our data suggest that increasing genetic abnormalities as described by the gene expression data are associated with increased risk for EM relapse.

Fujita Y, Yagishita S, Hagiwara K, et al.
The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer.
Mol Ther. 2015; 23(4):717-27 [PubMed] Free Access to Full Article Related Publications
Programmed cell death ligand-1 (PD-L1) has recently gained considerable attention for its role in tumor immune escape. Here, we identify a miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer (NSCLC), independent of immunoinhibitory signals. miR-197 is downregulated in platinum-resistant NSCLC specimens, resulting in the promotion of chemoresistance, tumorigenicity, and pulmonary metastasis in vitro and in vivo. Mechanistic investigations reveal that a miR-197-mediated CKS1B/STAT3 axis exerts tumor progression regulated by various oncogenic genes (Bcl-2, c-Myc, and cyclin D1), and PD-L1 is a putative biomarker of this axis. Furthermore, we demonstrate that a miR-197 mimic sensitizes PD-L1(high) drug-resistant cells to chemotherapy. These results indicate that the biological interaction between PD-L1 and chemoresistance occurs through the microRNA regulatory cascade. More importantly, expression levels of miR-197 are inversely correlated with PD-L1 expression (n = 177; P = 0.026) and are associated with worse overall survival (P = 0.015). Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.

Zhao H, Bauzon F, Bi E, et al.
Substituting threonine 187 with alanine in p27Kip1 prevents pituitary tumorigenesis by two-hit loss of Rb1 and enhances humoral immunity in old age.
J Biol Chem. 2015; 290(9):5797-809 [PubMed] Free Access to Full Article Related Publications
p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases. Inhibiting p27 protein degradation is an actively developing cancer therapy strategy. One focus has been to identify small molecule inhibitors to block recruitment of Thr-187-phosphorylated p27 (p27T187p) to SCF(Skp2/Cks1) ubiquitin ligase. Since phosphorylation of Thr-187 is required for this recruitment, p27T187A knockin (KI) mice were generated to determine the effects of systemically blocking interaction between p27 and Skp2/Cks1 on tumor susceptibility and other proliferation related mouse physiology. Rb1(+/-) mice develop pituitary tumors with full penetrance and the tumors are invariably Rb1(-/-), modeling tumorigenesis by two-hit loss of RB1 in humans. Immunization induced humoral immunity depends on rapid B cell proliferation and clonal selection in germinal centers (GCs) and declines with age in mice and humans. Here, we show that p27T187A KI prevented pituitary tumorigenesis in Rb1(+/-) mice and corrected decline in humoral immunity in older mice following immunization with sheep red blood cells (SRBC). These findings reveal physiological contexts that depend on p27 ubiquitination by SCF(Skp2-Cks1) ubiquitin ligase and therefore help forecast clinical potentials of Skp2/Cks1-p27T187p interaction inhibitors. We further show that GC B cells and T cells use different mechanisms to regulate their p27 protein levels, and propose a T helper cell exhaustion model resembling that of stem cell exhaustion to understand decline in T cell-dependent humoral immunity in older age.

Chayka O, D'Acunto CW, Middleton O, et al.
Identification and pharmacological inactivation of the MYCN gene network as a therapeutic strategy for neuroblastic tumor cells.
J Biol Chem. 2015; 290(4):2198-212 [PubMed] Free Access to Full Article Related Publications
The MYC family of transcription factors consists of three well characterized members, c-MYC, L-MYC, and MYCN, deregulated in the majority of human cancers. In neuronal tumors such as neuroblastoma, MYCN is frequently activated by gene amplification, and reducing its expression by RNA interference has been shown to promote growth arrest and apoptosis of tumor cells. From a clinical perspective, RNA interference is not yet a viable option, and small molecule inhibitors of transcription factors are difficult to develop. We therefore planned to identify, at the global level, the genes interacting functionally with MYCN required to promote fitness of tumor cells facing oncogenic stress. To find genes whose inactivation is synthetically lethal to MYCN, we implemented a genome-wide approach in which we carried out a drop-out shRNA screen using a whole genome library that was delivered into isogenic neuroblastoma cell lines expressing or not expressing MYCN. After the screen, we selected for in-depth analysis four shRNAs targeting AHCY, BLM, PKMYT1, and CKS1B. These genes were chosen because they are directly regulated by MYC proteins, associated with poor prognosis of neuroblastoma patients, and inhibited by small molecule compounds. Mechanistically, we found that BLM and PKMYT1 are required to limit oncogenic stress and promote stabilization of the MYCN protein. Cocktails of small molecule inhibitors of CKS1B, AHCY, BLM, and PKMYT1 profoundly affected the growth of all neuroblastoma cell lines but selectively caused death of MYCN-amplified cells. Our findings suggest that drugging the MYCN network is a promising avenue for the treatment of high risk, neuroblastic cancers.

Cheng XH, Black M, Ustiyan V, et al.
SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the Foxm1 oncogene.
PLoS Genet. 2014; 10(9):e1004656 [PubMed] Free Access to Full Article Related Publications
SAM-pointed domain-containing ETS transcription factor (SPDEF) is expressed in normal prostate epithelium. While its expression changes during prostate carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial due to the lack of genetic mouse models. In present study, we generated transgenic mice with the loss- or gain-of-function of SPDEF in prostate epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate cancer. Loss of SPDEF increased cancer progression and tumor cell proliferation, whereas over-expression of SPDEF in prostate epithelium inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in vitro. Transgenic over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a transcription factor critical for tumor cell proliferation, and reduced expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1 and Topo2alpha. Deletion of SPDEF in transgenic mice and cultures prostate tumor cells increased expression of Foxm1 and its target genes. Furthermore, an inverse correlation between SPDEF and Foxm1 levels was found in human prostate cancers. The two-gene signature of low SPDEF and high FoxM1 predicted poor survival in prostate cancer patients. Mechanistically, SPDEF bound to, and inhibited transcriptional activity of Foxm1 promoter by interfering with the ability of Foxm1 to activate its own promoter through auto-regulatory site located in the -745/-660 bp Foxm1 promoter region. Re-expression of Foxm1 restored cellular proliferation in the SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in mouse prostates. Altogether, SPDEF inhibits prostate carcinogenesis by preventing Foxm1-regulated proliferation of prostate tumor cells. The present study identified novel crosstalk between SPDEF tumor suppressor and Foxm1 oncogene and demonstrated that this crosstalk is required for tumor cell proliferation during progression of prostate cancer in vivo.

Kashkin K, Chernov I, Stukacheva E, et al.
Cancer specificity of promoters of the genes controlling cell proliferation.
J Cell Biochem. 2015; 116(2):299-309 [PubMed] Related Publications
Violation of proliferation control is a common feature of cancer cells. We put forward the hypothesis that promoters of genes involved in the control of cell proliferation should possess intrinsic cancer specific activity. We cloned promoter regions of CDC6, POLD1, CKS1B, MCM2, and PLK1 genes into pGL3 reporter vector and studied their ability to drive heterologous gene expression in transfected cancer cells of different origin and in normal human fibroblasts. Each promoter was cloned in short (335-800 bp) and long (up to 2.3 kb) variants to cover probable location of core and whole promoter regulatory elements. Cloned promoters were significantly more active in cancer cells than in normal fibroblasts that may indicate their cancer specificity. Both versions of CDC6 promoters were shown to be most active while the activities of others were close to that of BIRC5 gene (survivin) gene promoter. Long and short variants of each cloned promoter demonstrated very similar cancer specificity with the exception of PLK1-long promoter that was substantially more specific than its short variant and other promoters under study. The data indicate that most of the important cis-regulatory transcription elements responsible for intrinsic cancer specificity are located in short variants of the promoters under study. CDC6 short promoter may serve as a promising candidate for transcription targeted cancer gene therapy.

Stella F, Pedrazzini E, Baialardo E, et al.
Quantitative analysis of CKS1B mRNA expression and copy number gain in patients with plasma cell disorders.
Blood Cells Mol Dis. 2014; 53(3):110-7 [PubMed] Related Publications
In this study, we have examined CKS1B gene expression and copy number in a total of 114- patients at diagnosis: 83 with multiple myeloma (MM) and 31 with monoclonal gammopathy of undetermined significance (MGUS). Results were correlated with cytogenetics, FISH and clinical characteristic. Significant CKS1B mRNA levels in MM compared to MGUS cases (p<0.048) were detected. In MM, the frequency of 1q21 (CKS1B) copy gain was significantly higher in cases with abnormal karyotype compared to patients with normal karyotype (p=0.021). Global analysis showed a positive correlation between CKS1B expression and 1q21 copy number (p<0.0001). No association between CKS1B mRNA expression and clinical parameters was found. However, a significantly higher level of β2 microglobulin in cases with 1q21 gains than those without (p=0.0094) was observed. Overall survival was shorter in cases with 1q21 gain compared to those with normal 1q21 region (p=0.0082). Our results suggest a role for CKS1B in the multiple step process of progression of MGUS to MM and show that CKS1B copy gain has a more significant prognostic value than its overexpression. This adverse impact on survival probably reflects the genetic instability associated to chromosome 1q alterations resulting in a more aggressive behavior of the disease.

Salama ME, Du S, Efimova O, et al.
Neoplastic plasma cell aberrant antigen expression patterns and their association with genetic abnormalities.
Leuk Lymphoma. 2015; 56(2):426-33 [PubMed] Free Access to Full Article Related Publications
Little is known about aberrant antigen expression patterns and their association with cytogenetic aberrations in multiple myeloma (MM). We examined the correlation between flow cytometry and florescence in situ hybridization (FISH) in 167 marrow specimens with MM. Gene expression profiling of CD56, CD117, CD52 and CD20 mRNA in plasma cells (PCs) from patients treated on Total Therapy 2 and Total Therapy 3 trials were also evaluated. Higher expression of CD56 and CD117 was associated with hyperdiploidy. High CD52 mRNA expression was associated with c-MAF and FGFR3 subgroups. Higher expression of CD56 mRNA, but lower Kit expression, were noted in association with FGFR3. In contrast, the c-MAF subgroup showed high Kit expression but lacked NCAM mRNA expression. CKS1B amplification showed positive correlation with CD52 (p=0.0065) but negative correlation with CD20 (p=0.0207). These findings indicate that phenotypic differences in MM are associated with distinct genetic subgroups, which potentially has important diagnostic and prognostic value.

Xu H, Choe C, Shin SH, et al.
Silencing of KIF14 interferes with cell cycle progression and cytokinesis by blocking the p27(Kip1) ubiquitination pathway in hepatocellular carcinoma.
Exp Mol Med. 2014; 46:e97 [PubMed] Free Access to Full Article Related Publications
Although it has been suggested that kinesin family member 14 (KIF14) has oncogenic potential in various cancers, including hepatocellular carcinoma (HCC), the molecular mechanism of this potential remains unknown. We aimed to elucidate the role of KIF14 in hepatocarcinogenesis by knocking down KIF14 in HCC cells that overexpressed KIF14. After KIF14 knockdown, changes in tumor cell growth, cell cycle and cytokinesis were examined. We also examined cell cycle regulatory molecules and upstream Skp1/Cul1/F-box (SCF) complex molecules. Knockdown of KIF14 resulted in suppression of cell proliferation and failure of cytokinesis, whereas KIF14 overexpression increased cell proliferation. In KIF14-silenced cells, the levels of cyclins E1, D1 and B1 were profoundly decreased compared with control cells. Of the cyclin-dependent kinase inhibitors, the p27(Kip1) protein level specifically increased after KIF14 knockdown. The increase in p27(Kip1) was not due to elevation of its mRNA level, but was due to inhibition of the proteasome-dependent degradation pathway. To explore the pathway upstream of this event, we measured the levels of SCF complex molecules, including Skp1, Skp2, Cul1, Roc1 and Cks1. The levels of Skp2 and its cofactor Cks1 decreased in the KIF14 knockdown cells where p27(Kip1) accumulated. Overexpression of Skp2 in the KIF14 knockdown cells attenuated the failure of cytokinesis. On the basis of these results, we postulate that KIF14 knockdown downregulates the expression of Skp2 and Cks1, which target p27(Kip1) for degradation by the 26S proteasome, leading to accumulation of p27(Kip1). The downregulation of Skp2 and Cks1 also resulted in cytokinesis failure, which may inhibit tumor growth. To the best of our knowledge, this is the first report that has identified the molecular target and oncogenic effect of KIF14 in HCC.

Kim JY, Kim HJ, Park JH, et al.
Epidermal growth factor upregulates Skp2/Cks1 and p27(kip1) in human extrahepatic cholangiocarcinoma cells.
World J Gastroenterol. 2014; 20(3):755-73 [PubMed] Free Access to Full Article Related Publications
AIM: To evaluate the expression status of S-phase kinase-associated protein 2 (Skp2)/cyclin-dependent kinases regulatory subunit 1 (Cks1) and p27(kip1), and assess the prognostic significance of Skp2/Cks1 expression with p27(kip1) in patients with extrahepatic cholangiocarcinoma.
METHODS: Seventy-six patients who underwent curative resection for histologically confirmed extrahepatic cholangiocarcinoma at our institution from December 1994 to March 2008 were enrolled. Immunohistochemical staining for Skp2, Cks1, p27(kip1), and Ki67, along with other relevant molecular biologic experiments, were performed.
RESULTS: By Cox regression analyses, advanced age (> 65 years), advanced AJCC tumor stage, poorly differentiated histology, and higher immunostaining intensity of Skp2 were identified as independent prognostic factors in patients with extrahepatic cholangiocarcinoma. Exogenous epidermal growth factor (EGF, especially 0.1-10 ng/mL) significantly increased the proliferation indices by MTT assay and the mRNA levels of Skp2/Cks1 and p27(kip1) in SNU-1196, SNU-1079, and SNU-245 cells. The protein levels of Skp2/Cks1 (from nuclear lysates) and p27(kip1) (from cytosolic lysate) were also significantly increased in these cells. There were significant reductions in the protein levels of Skp2/Cks1 and p27(kip1) (from nuclear lysate) after the treatment of LY294002. By chromatin immunoprecipitation assay, we found that E2F1 transcription factor directly binds to the promoter site of Skp2.
CONCLUSION: Higher immunostaining intensity of Skp2/Cks1 was an independent prognostic factor for patients with extrahepatic cholangiocarcinoma. EGF upregulates the mRNA and protein levels of Skp2/Cks1 and p27(kip1) via the PI3K/Akt pathway and direct binding of E2F1 transcription factor with the Skp2 promoter.

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