Gene Summary

Gene:CDK1; cyclin dependent kinase 1
Aliases: CDC2, CDC28A, P34CDC2
Summary:The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is a catalytic subunit of the highly conserved protein kinase complex known as M-phase promoting factor (MPF), which is essential for G1/S and G2/M phase transitions of eukaryotic cell cycle. Mitotic cyclins stably associate with this protein and function as regulatory subunits. The kinase activity of this protein is controlled by cyclin accumulation and destruction through the cell cycle. The phosphorylation and dephosphorylation of this protein also play important regulatory roles in cell cycle control. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase 1
Source:NCBIAccessed: 31 August, 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 31 August 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.

  • Bladder Cancer
  • Staurosporine
  • Viral Matrix Proteins
  • Radiation Tolerance
  • Gene Expression Profiling
  • Lung Cancer
  • Triple Negative Breast Cancer
  • Cancer Gene Expression Regulation
  • Transcription
  • bcl-X Protein
  • Survival Rate
  • CDC2 Protein Kinase
  • Messenger RNA
  • Spermatogenesis
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Chromosome 10
  • Cyclin-Dependent Kinases
  • p53 Protein
  • Breast Cancer
  • Retinoic Acid
  • ral GTP-Binding Proteins
  • Topoisomerase II Inhibitors
  • p21-Activated Kinases
  • Proportional Hazards Models
  • Wound Healing
  • S-Phase Kinase-Associated Proteins
  • Purines
  • Wnt3 Protein
  • Sirolimus
  • Signal Transduction
  • Cell Cycle
  • Tumor Burden
  • X-Box Binding Protein 1
  • Roscovitine
  • Neoplasm Invasiveness
  • bcl-2-Associated X Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • Xanthones
  • Cell Cycle Proteins
  • Cell Proliferation
  • Apoptosis
  • SOXB1 Transcription Factors
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: CDK1 (cancer-related)

Liu S, Han Z, Trivett AL, et al.
Cryptotanshinone has curative dual anti-proliferative and immunotherapeutic effects on mouse Lewis lung carcinoma.
Cancer Immunol Immunother. 2019; 68(7):1059-1071 [PubMed] Free Access to Full Article Related Publications
Lung cancer is currently the leading cause of cancer-related mortality with very limited effective therapy. Screening of a variety of traditional Chinese medicines (TCMs) for their capacity to inhibit the proliferation of human lung cancer A549 cells and to induce the in vitro maturation of human DCs led to the identification of cryptotanshinone (CT), a compound purified from the TCM Salvia miltiorrhiza Bunge. Here, CT was shown to inhibit the proliferation of mouse Lewis lung carcinoma (LLC) cells by upregulating p53, downregulating cyclin B1 and Cdc2, and, consequently, inducing G2/M cell-cycle arrest of LLC cells. In addition, CT promoted maturation of mouse and human DCs with upregulation of costimulatory and MHC molecules and stimulated DCs to produce TNFα, IL-1β, and IL-12p70, but not IL-10 in vitro. CT-induced maturation of DCs depended on MyD88 and also involved the activation of NF-κB, p38, and JNK. CT was effective in the treatment of LLC tumors and, when used in combination with low doses of anti-PD-L1, cured LLC-bearing mice with the induction of subsequent anti-LLC long-term specific immunity. CT treatment promoted T-cell infiltration and elevated the expression of genes typical of Th1 polarization in LLC tumor tissue. The therapeutic effect of CT and low doses of anti-PD-L1 was reduced by depletion of CD4 and CD8 T cells. This paper provides the first report that CT induces immunological antitumor activities and may provide a new promising antitumor immunotherapeutic.

Rutz J, Maxeiner S, Juengel E, et al.
Growth and Proliferation of Renal Cell Carcinoma Cells Is Blocked by Low Curcumin Concentrations Combined with Visible Light Irradiation.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
The anti-cancer properties of curcumin in vitro have been documented. However, its clinical use is limited due to rapid metabolization. Since irradiation of curcumin has been found to increase its anti-cancer effect on several tumor types, this investigation was designed to determine whether irradiation with visible light may enhance the anti-tumor effects of low-dosed curcumin on renal cell carcinoma (RCC) cell growth and proliferation. A498, Caki1, and KTCTL-26 cells were incubated with curcumin (0.1⁻0.4 µg/mL) and irradiated with 1.65 J/cm² visible light for 5 min. Controls were exposed to curcumin or light alone or remained untreated. Curcumin plus light, but not curcumin or light exposure alone altered growth, proliferation, and apoptosis of all three RCC tumor cell lines. Cells were arrested in the G0/G1 phase of the cell cycle. Phosphorylated (p) CDK1 and pCDK2, along with their counter-receptors Cyclin B and A decreased, whereas p27 increased. Akt-mTOR-signaling was suppressed, the pro-apoptotic protein Bcl-2 became elevated, and the anti-apoptotic protein Bax diminished. H3 acetylation was elevated when cells were treated with curcumin plus light, pointing to an epigenetic mechanism. The present findings substantiate the potential of combining low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in RCC.

Piao J, Zhu L, Sun J, et al.
High expression of CDK1 and BUB1 predicts poor prognosis of pancreatic ductal adenocarcinoma.
Gene. 2019; 701:15-22 [PubMed] Related Publications
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer-related death. Increasing evidence suggests that cell cycle dysregulation is one of the hallmarks of cancer. In this study, by using the GEO database, we predicted the cell cycle-related protein CDK1 and BUB1 to be significantly overexpressed in PDAC tissues. Thus, this study aimed to investigate the clinical pathological significance of CDK1 and BUB1 in PDAC.
METHODS: To explore the role of CDK1 and BUB1 in PDAC progression and evaluate their prognostic value, we investigated the expression patterns of CDK1 and BUB1 by using immunohistochemical staining in 99 PDAC and 71 normal pancreatic tissues with complete pathological parameters and survival data.
RESULTS: CDK1 and BUB1 were significantly overexpressed in PDAC tissues. The expression of CDK1 was correlated with tumor size and histological grade, and the expression of BUB1 was correlated with the tumor size of PDAC. With regard to survival, a high expression of either CDK1 or BUB1 was correlated with a short survival of PDAC patients. Additionally, PDAC patients with a concurrent high expression of CDK1 and BUB1 showed the shortest survival.
CONCLUSIONS: Our study demonstrated that CDK1 and BUB1 may play a role in PDAC progression and could be prognostic biomarkers for PDAC patients.

Jonsson M, Fjeldbo CS, Holm R, et al.
Mitochondrial Function of CKS2 Oncoprotein Links Oxidative Phosphorylation with Cell Division in Chemoradioresistant Cervical Cancer.
Neoplasia. 2019; 21(4):353-362 [PubMed] Free Access to Full Article Related Publications
CDK regulatory subunit 2 (CKS2) has a nuclear function that promotes cell division and is a candidate biomarker of chemoradioresistance in cervical cancer. The underlying mechanisms are, however, not completely understood. We investigated whether CKS2 also has a mitochondrial function that augments tumor aggressiveness. Based on global gene expression data of two cervical cancer cohorts of 150 and 135 patients, we identified a set of genes correlated with CKS2 expression. Gene set enrichment analysis showed enrichment of mitochondrial cellular compartments, and the hallmarks oxidative phosphorylation (OXPHOS) and targets of the MYC oncogene in the gene set. By in situ proximity ligation assay, we showed that CKS2 formed complex with the positively correlated MYC target, mitochondrial single-stranded DNA binding protein SSBP1, in the mitochondrion of cervix tumor samples and HeLa and SiHa cervical cancer cell lines, indicating a role in mitochondrial DNA (mtDNA) replication and thereby OXPHOS. CDK1 was found to be part of the complex. Flow cytometry analyses of HeLa cells showed cell cycle regulation of the CKS2-SSBP1 complex consistent with mtDNA replication activity. Moreover, repression of mtDNA replication and OXPHOS by acute hypoxia decreased CKS2-SSBP1 complex abundance and expression of MYC targets. By immunohistochemistry, cytoplasmic CKS2 expression was found to add to the prognostic impact of nuclear CKS2 expression in patients, suggesting that the mitochondrial function promotes tumor aggressiveness. Our study uncovers a novel link between regulation of cell division by nuclear pathways and OXPHOS in the mitochondrion that involves CKS2 and promotes chemoradioresistance of cervical cancer.

Liu Y, Wang Y, Yu S, et al.
The Role and Mechanism of CRT0066101 as an Effective Drug for Treatment of Triple-Negative Breast Cancer.
Cell Physiol Biochem. 2019; 52(3):382-396 [PubMed] Related Publications
BACKGROUND/AIMS: Breast cancer is clinically classified into three main subtypes: estrogen receptor-positive (ER
METHODS: The expression level of PRKDs was analyzed in breast cancer samples and breast cancer cell lines. The effects of inhibiting PRKD activity with CRT0066101 on TNBC cell proliferation, cell cycle, apoptosis, and tumor growth were studied by Cell Counting Kit8 assay, cell cycle assay, propidium iodide/annexin-V assay, and a xenograft mouse model, respectively. To uncover the molecular mechanism of CRT0066101 in TNBC, comparative phosphoproteomic analysis using iTRAQ was employed.
RESULTS: We found that PRKD2 and PRKD3 were preferentially expressed in breast cancers. Immunohistochemistry confirmed the overexpression of PRKD2 and PRKD3 in TNBC. CRT0066101, which inhibited the activity of PRKDs, dramatically inhibited proliferation, increased apoptosis and the G1-phase population of TNBC cells in vitro, and reduced breast tumor volume in vivo. Comparative phosphoproteomic analysis between breast cancer cells with and without CRT0066101 treatment revealed that the anti-breast cancer effects involved regulation of a complex network containing multiple enriched pathways and several hub-nodes contributing to multiple cancer-related processes, thus explaining the described effects of CRT0066101 on TNBC in vitro and in vivo. Finally, we validated several targets of PRKD inhibition by treatment with CRT0066101 and small interfering RNAs against PRKD2 and PRKD3 (siPRKD2 and siPRKD3), including p-MYC(T58/ S62), p-MAPK1/3(T202/Y204), p-AKT(S473), p-YAP(S127), and p-CDC2(T14).
CONCLUSION: PRKD inhibitor CRT0066101 exhibits anti-TNBC effects via modulating a phosphor-signaling network and inhibiting the phosphorylation of many cancer-driving factors, including MYC, MAPK1/3, AKT, YAP, and CDC2, providing insight into the important roles as well as the molecular mechanism of CRT0066101 as an effective drug for TNBC.

Suh SS, Hong JM, Kim EJ, et al.
Antarctic freshwater microalga,
Int J Med Sci. 2019; 16(2):189-197 [PubMed] Free Access to Full Article Related Publications
Inflammation triggered by the innate immune system is a strategy to protect organisms from the risk of environmental infection. However, it has recently become clear that inflammation can cause a variety of human diseases, including cancer. In this study, we investigated the effects of an ethanol extract of the Antarctic freshwater microalgae,

Wu M, Liu Z, Zhang A, Li N
Identification of key genes and pathways in hepatocellular carcinoma: A preliminary bioinformatics analysis.
Medicine (Baltimore). 2019; 98(5):e14287 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. However, the precise mechanisms of the development and progression of HCC remain unclear. The present study attempted to identify and functionally analyze the differentially expressed genes between HCC and cirrhotic tissues by using comprehensive bioinformatics analyses.
METHODS: The GSE63898 gene expression profile was downloaded from the Gene Expression Omnibus (GEO) and analyzed using the online tool GEO2R to identify differentially expressed genes (DEGs). Gene ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs were performed in DAVID. The STRING database was used to evaluate the interactions of DEGs and to construct a protein-protein interaction (PPI) network using Cytoscape software. Hub genes were selected using the cytoHubba plugin and were validated with the cBioPortal database.
RESULTS: A total of 301 DEGs were identified between HCC and cirrhotic tissues. The GO analysis results showed that these DEGs were significantly enriched in certain biological processes including negative regulation of growth and cell chemotaxis. Several significant pathways, including the p53 signaling pathway, were identified as being closely associated with these DEGs. The top 12 hub genes were screened and included TTK, NCAPG, TOP2A, CCNB1, CDK1, PRC1, RRM2, UBE2C, ZWINT, CDKN3, AURKA, and RACGAP1. The cBioPortal analysis found that alterations in hub genes could result in significantly reduced disease-free survival in HCC.
CONCLUSION: The present study identified a series of key genes and pathways that may be involved in the tumorigenicity and progression of HCC, providing a new understanding of the underlying molecular mechanisms of carcinogenesis in HCC.

Bai H, Chang Y, Li B, et al.
Effects of lentivirus-mediated astrocyte elevated gene-1 overexpression on proliferation and apoptosis of human retinoblastoma cells.
Acta Ophthalmol. 2019; 97(3):e397-e402 [PubMed] Related Publications
PURPOSE: To investigate the effect of astrocyte elevated gene-1 (AEG-1) overexpression on the biological behaviour of human retinoblastoma (RB) cells and its possible mechanism.
METHODS: Three human RB cell lines (SO-RB50, Y79 and WERI-RB1) were infected with AEG-1-GFP recombinant lentiviral vectors to induce AEG-1 overexpression, while the cells infected with negative lentiviral vectors and cells without any intervention formed control groups.
RESULTS: All three RB cell lines showed an overexpression of AEG-1 after lentivirus infection (p < 0.001 for all three cell lines). The survival rate of RB cells increased (all p < 0.001) in the AEG-1 overexpressed groups when compared with the control groups. There was a decrease in G0/G1 cell cycle phase arrest and an accumulation in G2/M cell cycle phase in all three RB cell lines (p < 0.001), with an induction in the S phase in WERI-RB1 cells. It was paralleled by a downregulation of p21 and p27 proteins and an upregulation of the Cdc2 protein. The apoptosis rate of RB cells declined (p < 0.001) when AEG-1 was overexpressed, in association with an upregulation of Bcl-2 protein and a downregulation of Bax protein and cleaved caspase-3 proteins.
CONCLUSIONS: A lentivirus-mediated AEG-1 overexpression in RB cells led in vitro to a growth promotion and an apoptosis inhibition of human RB cells, associated with an upregulation of the Bcl-2 protein, a downregulation of the Bax protein and of cleaved caspase-3 proteins, and with alterations of the cell cycle. AEG-1 may be involved in the development and progression of RB.

Shaabanpour Aghamaleki F, Mollashahi B, Aghamohammadi N, et al.
Bioinformatics Analysis of Key Genes and Pathways for Medulloblastoma as a Therapeutic Target
Asian Pac J Cancer Prev. 2019; 20(1):221-227 [PubMed] Free Access to Full Article Related Publications
Introduction: One of the major challenges in cancer treatment is the lack of specific and accurate treatment in cancer. Data analysis can help to understand the underlying molecular mechanism that leads to better treatment. Increasing availability and reliability of DNA microarray data leads to increase the use of these data in a variety of cancers. This study aimed at applying and evaluating microarray data analyzing, identification of important pathways and gene network for medulloblastoma patients to improve treatment approaches especially target therapy. Methods: In the current study, Microarray gene expression data (GSE50161) were extracted from Geo datasets and then analyzed by the affylmGUI package to predict and investigate upregulated and downregulated genes in medulloblastoma. Then, the important pathways were determined by using software and gene enrichment analyses. Pathways visualization and network analyses were performed by Cytoscape. Results: A total number of 249 differentially expressed genes (DEGs) were identified in medulloblastoma compared to normal samples. Cell cycle, p53, and FoxO signaling pathways were indicated in medulloblastoma, and CDK1, CCNB1, CDK2, and WEE1 were identified as some of the important genes in the medulloblastoma. Conclusion: Identification of critical and specific pathway in any disease, in our case medulloblastoma, can lead us to better clinical management and accurate treatment and target therapy.

Mohanta S, Sekhar Khora S, Suresh A
Cancer Stem Cell based molecular predictors of tumor recurrence in Oral squamous cell carcinoma.
Arch Oral Biol. 2019; 99:92-106 [PubMed] Related Publications
OBJECTIVE: This study aimed to identify the cancer stem cell specific biomarkers that can be effective candidate prognosticators of oral squamous cell carcinoma.
DESIGN: Microarray-based meta-analysis derived transcriptional profile of head and neck cancers was compared with the Cancer Stem Cell database to arrive at a subset of markers. This subset was further co-related with clinico-pathological parameters, recurrence and survival of oral cancer patients (n = 313) in The Cancer Genome Atlas database and in oral cancer (n = 28) patients.
RESULTS: Meta-analysis in combination with database comparison identified a panel of 221 genes specific to head and neck cancers. Correlation of expression levels of these markers in the oral cancer cohort of The Cancer Genome Atlas (n = 313) with treatment outcome identified 54 genes (p < 0.05 or fold change >2) associated with disease recurrence, 8 genes (NQO1, UBE2C, EDNRB, FKBP4, STAT3, HOXA1, RIT1, AURKA) being significant with high fold change. Assessment of the efficacy of the subset (n = 54) as survival predictors identified an additional 4 genes (CDK1, GINS2, PHF5 A, ERBB2) that co-related with poor disease-free survival (p < 0.05). CDK1 showed a significant association with the clinical stage, margin status and with advanced pathological parameters. Initial patient validation indicated that CDK1 and NQO1 significantly co-related with the poor disease-free and overall survival (p < 0.05).
CONCLUSION: This panel of oral cancer specific, cancer stem cell associated markers identified in this study, a subset of which was validated, will be of clinical benefit subject to large scale validation studies.

Chen S, Zhao Y, Shen F, et al.
Introduction of exogenous wild‑type p53 mediates the regulation of oncoprotein 18/stathmin signaling via nuclear factor‑κB in non‑small cell lung cancer NCI‑H1299 cells.
Oncol Rep. 2019; 41(3):2051-2059 [PubMed] Related Publications
Our previous studies demonstrated that high expression of oncoprotein 18 (Op18)/stathmin promotes malignant transformation of non‑small cell lung cancer NCI‑H1299 cells. Investigation of the cellular settings determined that NCI‑H1299 cells were genetically p53 deficient. In order to determine whether p53 deficiency is associated with Op18/stathmin‑mediated high levels of malignancy, exogenous wild‑type p53 (p53wt) was introduced into NCI‑H1299 cells in the present study to observe Op18/stathmin signaling changes and malignant behaviors. The results indicated that p53 downregulated Op18/stathmin expression and phosphorylation at the Ser25 and Ser63 sites in NCI‑H1299 cells, and the abilities of proliferation, colony formation and migration in multi‑dimensional spaces were simultaneously reduced. Introduction of p53wt inhibited the expression of the transcription factor nuclear factor‑κB (NF‑κB), and the activities of the Op18/stathmin upstream kinases cyclin‑dependent 2 (CDC2) and extracellular signal‑regulated kinase (ERK). Furthermore, blocking of NF‑κB signaling decreased CDC2 and ERK activation. Additionally, p53 intervention attenuated the secretion and protein expression of the immune inhibitory cytokine interleukin‑10, which was in accordance with the effect of NF‑κB signaling inhibition. Further experiments validated that p53 enhanced the sensitivity of NCI‑H1299 cells to Taxol through initiating the caspase‑3 and ‑9 intrinsic death pathways, and resulted in cell cycle arrest at the G1/S phases. These data indicated that exogenous p53wt mediates the regulation of Op18/stathmin signaling through the p53‑NF‑κB‑CDC2/ERK‑Op18/stathmin pathway, and that p53 deficiency is associated with high malignancy levels of NCI‑H1299 cells.

Roskoski R
Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs.
Pharmacol Res. 2019; 139:471-488 [PubMed] Related Publications
Cyclins and cyclin-dependent protein kinases (CDKs) are important proteins that are required for the regulation and expression of the large number of components necessary for the passage through the cell cycle. The concentrations of the CDKs are generally constant, but their activities are controlled by the oscillation of the cyclin levels during each cell cycle. Additional CDK family members play significant roles in a wide range of activities including gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1-phase of the cell cycle produce D type cyclins that activate CDK4/6. These activated enzymes catalyze the monophosphorylation of the retinoblastoma protein. Subsequently, CDK2-cyclin E catalyzes the hyperphosphorylation of Rb that promotes the release and activation of the E2F transcription factor, which in turn lead to the biosynthesis of dozens of proteins required for cell cycle progression. Consequently, cells pass the G1-restriction point and are committed to complete cell division in the absence of mitogenic stimulation. CDK2-cyclin A, CDK1-cyclin A, and CDK1-cyclin B are required for S-, G2-, and M-phase progression. A crucial mechanism in controlling cell cycle progression is the precise timing of more than 32,000 phosphorylation and dephosphorylation reactions catalyzed by a network of protein kinases and phosphoprotein phosphatases as determined by mass spectrometry. Increased cyclin or CDK expression or decreased levels of endogenous CDK modulators/inhibitors such as INK4 or CIP/KIP have been observed in a wide variety of carcinomas, hematological malignancies, and sarcomas. The pathogenesis of neoplasms because of mutations in the CDKs are rare. Owing to their role in cell proliferation, CDKs represent natural targets for anticancer therapies. Palbociclib, ribociclib, and abemaciclib are FDA-approved CDK4/6 inhibitors used in the treatment of breast cancer. These drugs have IC

Zhang X, Pan Y, Fu H, Zhang J
Nucleolar and Spindle Associated Protein 1 (NUSAP1) Inhibits Cell Proliferation and Enhances Susceptibility to Epirubicin In Invasive Breast Cancer Cells by Regulating Cyclin D Kinase (CDK1) and DLGAP5 Expression.
Med Sci Monit. 2018; 24:8553-8564 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Differentially expressed genes (DEGs) of IBC were selected from the Gene Expression Omnibus (GEO) chip data: GSE21422 and GSE21974. Network analysis of the DEGs and IBC-related genes was performed in STRING database to find the core gene. Thus, this study aimed to determine the role of NUSAP1 in invasive breast cancer (IBC) and to investigate its effect on drug susceptibility to epirubicin (E-ADM). MATERIAL AND METHODS The mRNA expression of NUSAP1 was determined by quantitative polymerase chain reaction (q-PCR). The protein expression was detected by Western blotting. Cell growth and growth cycle were detected by MTT assay and flow cytometry, respectively. Cell migration and invasion were tested by Transwell assay. RESULTS Through use of gene network analysis, we found that NUSAP1 interacts with IBC-related genes. NUSAP1 presented high expression in IBC tissue samples and MCF-7 cells. NUSAP1 overexpression promoted the growth, migration, and invasion of MCF-7 cells. While NUSAP1 gene silencing downregulated the expression of genes associated with cell cycle progression in G2/M phase, cyclin D kinase (CDK1) and DLGAP5 arrested cells in G2/M phase and significantly inhibited the growth, migration, and invasion of MCF-7 cells. si-NUSAP1 increased the susceptibility of MCF-7 cells to E-ADM-induced apoptosis. CONCLUSIONS Our study provides evidence that downregulation of NUSAP1 can inhibit the proliferation, migration, and invasion of IBC cells by regulating CDK1 and DLGAP5 expression and enhances the drug susceptibility to E-ADM.

Xu Q, Li M, Yang M, et al.
α-pinene regulates
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
The naturally occurring compound α-pinene induces cell cycle arrest and antitumor activity. We examined effects of α-pinene on cell cycle regulation in hepatocellular carcinoma cells (HepG2) cells to establish a foundation for its development as a novel treatment for hepatocellular carcinoma (HCC). HepG2 cells treated with α-pinene exhibited dose-dependent growth inhibition as a result of G

Chen M, Yin X, Lu C, et al.
Mahanine induces apoptosis, cell cycle arrest, inhibition of cell migration, invasion and PI3K/AKT/mTOR signalling pathway in glioma cells and inhibits tumor growth in vivo.
Chem Biol Interact. 2019; 299:1-7 [PubMed] Related Publications
Gliomas are among the most frequent types of primary malignancies in the central nervous system. The main treatment for glioma includes surgical resection followed by a combination of radiotherapy and chemotherapy. Despite the availability of several treatments, the average survival for patients with glioma at advanced stages still remains 16 months only. Therefore, there is an urgent need to look for novel and more efficient drug candidates for the treatment of glioma. In the current study the anticancer activity of Mahanine was evaluated against a panel of glioma cells. The results revealed that Mahanine exerted significant anticancer effects on the glioma HS 683 cells with an IC

Geng RX, Li N, Xu Y, et al.
Identification of Core Biomarkers Associated with Outcome in Glioma: Evidence from Bioinformatics Analysis.
Dis Markers. 2018; 2018:3215958 [PubMed] Free Access to Full Article Related Publications
Glioma is the most common neoplasm of the central nervous system (CNS); the progression and outcomes of which are affected by a complicated network of genes and pathways. We chose a gene expression profile of GSE66354 from GEO database to search core biomarkers during the occurrence and development of glioma. A total of 149 samples, involving 136 glioma and 13 normal brain tissues, were enrolled in this article. 1980 differentially expressed genes (DEGs) including 697 upregulated genes and 1283 downregulated genes between glioma patients and healthy individuals were selected using GeoDiver and GEO2R tool. Then, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) plug-in was employed to imagine protein-protein interaction (PPI) of these DEGs. The upregulated genes were enriched in cell cycle, ECM-receptor interaction, and p53 signaling pathway, while the downregulated genes were enriched in retrograde endocannabinoid signaling, glutamatergic synapse, morphine addiction, GABAergic synapse, and calcium signaling pathway. Subsequently, 4 typical modules were discovered by the PPI network utilizing MCODE software. Besides, 15 hub genes were chosen according to the degree of connectivity, including TP53, CDK1, CCNB1, and CCNB2, the Kaplan-Meier analysis of which was further identified. In conclusion, this bioinformatics analysis indicated that DEGs and core genes, such as TP53, might influence the development of glioma, especially in tumor proliferation, which were expected to be promising biomarkers for diagnosis and treatment of glioma.

Rutz J, Juengel E, Euler S, et al.
Chronic Sulforaphane Application Does Not Induce Resistance in Renal Cell Carcinoma Cells.
Anticancer Res. 2018; 38(11):6201-6207 [PubMed] Related Publications
BACKGROUND/AIM: Since the natural compound sulforaphane (SFN) has been shown to stop tumor growth, renal cell carcinoma (RCC) patients often use this drug in addition to their prescribed oncotherapy. The aim of this study was to examine whether resistance to SFN may develop after long-term application.
MATERIALS AND METHODS: Several RCC cell lines were incubated with SFN for short periods of time (24-72 h) or long periods of time (8 weeks) and cell growth, proliferation, and cell-cycle proteins were analyzed.
RESULTS: Both short- and long-term application of SFN distinctly reduced RCC cell growth and proliferation. However, differences in the distribution of cells in each phase of the cell cycle and in the expression of cell-cycle proteins were apparent. Short-term treatment induced S-phase arrest, whereas long-term treatment induced G
CONCLUSION: Chronic use of SFN did not evoke resistance, but differentially altered signaling pathways, compared to short-term use.

Sun C, Cheng X, Wang C, et al.
Gene expression profiles analysis identifies a novel two-gene signature to predict overall survival in diffuse large B-cell lymphoma.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy, however, specific tumor-associated genes and signaling pathways are yet to be deciphered. Differentially expressed genes (DEGs) were computed based on gene expression profiles from GSE32018, GSE56315, and The Cancer Genome Atlas (TCGA) DLBC. Overlapping DEGs were then evaluated for gene ontology (GO), pathways enrichment, DNA methylation, protein-protein interaction (PPI) network analysis as well as survival analysis. Seventy-four up-regulated and 79 down-regulated DEGs were identified. From PPI network analysis, majority of the DEGs were involved in cell cycle, oocyte meiosis, and epithelial-to-mesenchymal transition (EMT) pathways. Six hub genes including

Guo XX, Li XP, Zhou P, et al.
Evodiamine Induces Apoptosis in SMMC-7721 and HepG2 Cells by Suppressing NOD1 Signal Pathway.
Int J Mol Sci. 2018; 19(11) [PubMed] Free Access to Full Article Related Publications
Hepatocellular cancer (HCC) is a lethal malignancy with poor prognosis and easy recurrence. There are few agents with minor toxic side effects that can be used for treatment of HCC. Evodiamine (Evo), one of the major bioactive components derived from fructus

Zhuang L, Yang Z, Meng Z
Upregulation of BUB1B, CCNB1, CDC7, CDC20, and MCM3 in Tumor Tissues Predicted Worse Overall Survival and Disease-Free Survival in Hepatocellular Carcinoma Patients.
Biomed Res Int. 2018; 2018:7897346 [PubMed] Free Access to Full Article Related Publications
Objective: To evaluate the association between upregulated differentially expressed genes (DEGs) and the outcomes of patients with hepatocellular carcinoma (HCC).
Methods: Using Gene Expression Omnibus (GEO) datasets including GSE45436, GSE55092, GSE60502, GSE84402, and GSE17548, we detected upregulated DEGs in tumors. KEGG, GO, and Reactome enrichment analysis of the DEGs was conducted to clarify their function. The impact of the upregulated DEGs on patients' survival was analyzed based on TCGA profile.
Results: 161 shared upregulated DEGs were identified among GSE45436, GSE55092, GSE60502, and GSE84402 profiles. Cell cycle was the shared pathway/biological process in the gene sets investigation among databases of KEGG, GO, and Reactome. After being validated in GSE17548, 13 genes including BUB1B, CCNA2, CCNB1, CCNE2, CDC20, CDC6, CDC7, CDK1, CDK4, CDKN2A, CHEK1, MAD2L1, and MCM3 in cell cycle pathway were shared in the three databases for enrichment. The expression of BUB1B, CCNB1, CDC7, CDC20, and MCM3 was upregulated in HCC tissues when compared with adjacent normal tissues in 6.67%, 7.5%, 8.06%, 5.56%, and 9.72% of HCC patients, respectively. Overexpression of BUB1B, CCNB1, CDC7, CDC20, and MCM3 in HCC tissues accounted for poorer overall survival (OS) and disease-free survival (DFS) in HCC patients (all log rank
Conclusion: Correlated with advanced histologic grade and/or vascular invasion, upregulation of BUB1B, CCNB1, CDC7, CDC20, and MCM3 in HCC tissues predicted worse OS and DFS in HCC patients. These genes could be novel therapeutic targets for HCC treatment.

Gao X, Wang X, Zhang S
Bioinformatics identification of crucial genes and pathways associated with hepatocellular carcinoma.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Up to date, HCC pathogenesis has not been fully understood. The aim of the present study was to identify crucial genes and pathways associated with HCC by bioinformatics methods. The differentially expressed genes (DEGs) between 14 HCC tissues and corresponding non-cancerous tissues were identified using limma package. Gene Ontology (GO) and KEGG pathway enrichment analysis of DEGs were performed by clusterProfiler package. The protein-protein interaction (PPI) network of DEGs was constructed and visualized by STRING database and Cytoscape software, respectively. The crucial genes in PPI network were identified using a Cytoscape plugin, CytoNCA. Furthermore, the effect of the expression level of the crucial genes on HCC patient survival was analyzed by an interactive web-portal, UALCAN. A total of 870 DEGs including 237 up-regulated and 633 down-regulated genes were identified in HCC tissues. KEGG pathway analysis revealed that DEGs were mainly enriched in complement and coagulation cascades pathway, chemical carcinogenesis pathway, retinol metabolism pathway, fatty acid degradation pathway, and valine, leucine and isoleucine degradation pathway. PPI network analysis showed that

Lin J, Hou Y, Huang S, et al.
Exportin-T promotes tumor proliferation and invasion in hepatocellular carcinoma.
Mol Carcinog. 2019; 58(2):293-304 [PubMed] Free Access to Full Article Related Publications
Exportin-T (XPOT) belongs to the RAN-GTPase exportin family that mediates export of tRNA from the nucleus to the cytoplasm. Up-regulation of XPOT indicates poor prognosis in breast cancer patients. However, the correlation between XPOT and hepatocellular carcinoma (HCC) remains unclear. Here, we found that high expression of XPOT in HCC indicated worse prognosis via bioinformatics analysis. Consistently, immunohistochemical staining of 95 pairs of tumors and adjacent normal liver tissues (ANLT) also showed up-regulation of XPOT. Small interfering (si) RNA transfection was used to down-regulate XPOT in HepG2 and 7721 cell lines. Cell Counting Kit-8 (CCK8) assays were performed to analyze cell proliferation. Cell migration and invasion were measured by scratch wound healing assays and migration assays. Subcutaneous xenograft models were using to explore the role of XPOT in tumor formation in vivo. Down-regulation of XPOT significantly inhibited tumor proliferation and invasion in vitro and vivo. Gene set enrichment analysis (GSEA) results indicated that XPOT may affect tumor progression through cell cycle and ubiquitin-mediated proteolysis. Furthermore, knockdown of XPOT caused a block in G0/G1 phase as evidenced by down-regulation of cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), CyclinA1 (CCNA1), CyclinB1 (CCNB1), CyclinB2 (CCNB2), and CyclinE2 (CCNE2) in HCC cells. In conclusion, our findings indicate that XPOT could serve as a novel biomarker for prognoses and a potential therapeutic target for patients with HCC.

Greenleaf AL
Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium.
Transcription. 2019; 10(2):91-110 [PubMed] Article available free on PMC after 22/10/2019 Related Publications
As the new millennium began, CDK12 and CDK13 were discovered as nucleotide sequences that encode protein kinases related to cell cycle CDKs. By the end of the first decade both proteins had been qualified as CTD kinases, and it was emerging that both are heterodimers containing a Cyclin K subunit. Since then, many studies on CDK12 have shown that, through phosphorylating the CTD of transcribing RNAPII, it plays critical roles in several stages of gene expression, notably RNA processing; it is also crucial for maintaining genome stability. Fewer studies on CKD13 have clearly shown that it is functionally distinct from CDK12. CDK13 is important for proper expression of a number of genes, but it also probably plays yet-to-be-discovered roles in other processes. This review summarizes much of the work on CDK12 and CDK13 and attempts to evaluate the results and place them in context. Our understanding of these two enzymes has begun to mature, but we still have much to learn about both. An indicator of one major area of medically-relevant future research comes from the discovery that CDK12 is a tumor suppressor, notably for certain ovarian and prostate cancers. A challenge for the future is to understand CDK12 and CDK13 well enough to explain how their loss promotes cancer development and how we can intercede to prevent or treat those cancers. Abbreviations: CDK: cyclin-dependent kinase; CTD: C-terminal repeat domain of POLR2A; CTDK-I: CTD kinase I (yeast); Ctk1: catalytic subunit of CTDK-I; Ctk2: cyclin-like subunit of CTDK-I; PCAP: phosphoCTD-associating protein; POLR2A: largest subunit of RNAPII; SRI domain: Set2-RNAPII Interacting domain.

Saitoh Y, Bureta C, Sasaki H, et al.
The histone deacetylase inhibitor LBH589 inhibits undifferentiated pleomorphic sarcoma growth via downregulation of FOS-like antigen 1.
Mol Carcinog. 2019; 58(2):234-246 [PubMed] Related Publications
Undifferentiated pleomorphic sarcoma (UPS) is the second most frequent soft tissue sarcoma. Because of its resistance to chemotherapy, UPS patients are treated with surgical resection and complementary radiotherapy. However, since standard chemotherapy has not been established, unresectable or metastatic cases result in a poor prognosis. Therefore, the identification of a more effective therapy for UPS patients is needed. The development and progression of malignant tumors involve epigenetic alterations, and histone deacetylases (HDAC) have become a promising chemotherapeutic target. In this study, we investigated the potential effects and mechanisms of an HDAC inhibitor, LBH589, in UPS cells. We confirmed that LBH589 exhibits potent antitumor activities in four human UPS cell lines (GBS-1, TNMY-1, Nara-F, and Nara-H) and IC

Li Q, Wang W, Hu YC, et al.
Knockdown of Ubiquitin Associated Protein 2-Like (UBAP2L) Inhibits Growth and Metastasis of Hepatocellular Carcinoma.
Med Sci Monit. 2018; 24:7109-7118 [PubMed] Article available free on PMC after 22/10/2019 Related Publications
BACKGROUND The aim of this study was to explore the influence of ubiquitin associated protein 2-like (UBAP2L) on the growth and metastasis of hepatocellular carcinoma (HCC) and its potential underlying mechanism. MATERIAL AND METHODS UBAP2L gene was knocked down in SMMC-7721 by RNA interference and cell function experiments were performed. A subcutaneous xenograft tumor model was constructed to examine the effect of UBAP2L silence on HCC growth. Finally, the whole genomic microarrays were used to screen the potential mechanism of UBAP2L in regulating the biological function of HCC. RESULTS Compared with those in the control group, the cell proliferation and clone formation were significantly reduced, cell cycle was arrested in G2/M phase, the number of apoptotic cells was remarkably increased, and the abilities of vascular formation and cell migration and metastasis were dramatically weakened in the shUBAP2L group (All P<0.05). UBAP2L knockdown significantly suppressed the tumor growth of HCC in vivo. Moreover, a total of 320 genes changed significantly after UBAP2L knockdown, among which, 159 genes were upregulated and 161 genes were downregulated. Then, gene enrichment analysis revealed that PI3K/AKT and P53 signal pathway were the most significant in the top 10 enrichments. Finally, Western blot analysis verified that UBAP2L knockdown caused the increase of P21 and PTEN and decrease of CDK1, CCNB1, p-PI3K, and p-AKT. CONCLUSIONS UBAP2L plays an oncogenic role in HCC, and knockdown of its expression significantly inhibits HCC growth and metastasis, which may be related to the regulation of PI3K/AKT and P53 signaling pathways by UBAP2L.

Xie D, Song H, Wu T, et al.
MicroRNA‑424 serves an anti‑oncogenic role by targeting cyclin‑dependent kinase 1 in breast cancer cells.
Oncol Rep. 2018; 40(6):3416-3426 [PubMed] Article available free on PMC after 22/10/2019 Related Publications
The aim of the present study was to define the function of microRNA‑424‑5p (miR‑424) in breast cancer cells. The present study investigated the level and the potential function of miR‑424 in breast cancer by reverse transcription‑quantitative polymerase chain reaction assays. miR‑424 expression was decreased in the majority of human breast cancer specimens and cell lines used in the present study. The MTT assay, plate colony formation assay and flow cytometry analyses were used to characterize the function of miR‑424 in two types of breast cancer cell lines. Upregulation of miR‑424 inhibited cellular proliferation and regulated the cell cycle by arresting cells in the G2/M cell phase. The dual‑luciferase reporter assay was used to confirm the direct association between miR‑424 and cyclin‑dependent kinase 1 (CDK1). Silencing of CDK1 expression by CDK1 short interfering RNA also significantly suppressed cell proliferation and arrested cells in the G2/M cell phase. The results of the present study indicated that miR‑424 can suppress cell proliferation and arrest cells in G2/M cell phase by negatively regulating CDK1 mRNA in human breast cancer, possibly through the Hippo pathway and the extracellular signal‑regulated kinase pathway. The results of the present study provided novel evidence for the role of miR‑424 in breast cancer.

Cai JY, Xu TT, Wang Y, et al.
Histone deacetylase HDAC4 promotes the proliferation and invasion of glioma cells.
Int J Oncol. 2018; 53(6):2758-2768 [PubMed] Related Publications
Glioma is the most lethal type of primary brain tumor characterized by aggressiveness and a poor prognosis. Histone deacetylase 4 (HDAC4) is frequently dysregulated in human malignancies. However, its biological functions in the development of glioma are not fully understood. The present study aimed to evaluate HDAC4 expression in human glioma and to elucidate the mechanistic role of HDAC4 in glioma. The results suggested that HDAC4 was significantly upregulated in glioma tissues and a number of glioma cell lines compared with adjacent non-tumor tissues and the non-cancerous human glial cell line SVG p12, respectively (P<0.05). The proliferation, adenosine triphosphate (ATP) levels and invasion ability were substantially enhanced in U251 cells with HDAC4 overexpression, and suppressed in U251 cells with a knockdown of HDAC4 compared with that in U251 cells transfected with the negative control. Knockdown of HDAC4 resulted in cell cycle arrest at the G0/G1 phase and induced the increase of reactive oxygen species level in U251 cells. Furthermore, HDAC4 overexpression was revealed to substantially inhibit the expression of cyclin-dependent kinase (CDK) inhibitors p21 and p27, and the expression of E-cadherin and β‑catenin in glioma U251 cells. Knockdown of HDAC4 substantially promoted the expression of CDK1 and CDK2 and vimentin in glioma U251 cells. Mechanistically, the results of the present study demonstrated that HDAC4 displayed a significant upregulation in glioma, and promoted glioma cell proliferation and invasion mediated through the repression of p21, p27, E-cadherin and β‑catenin, and the potentiation of CDK1, CDK2 and vimentin. Altogether, the present study revealed that HDAC4 overexpression was central for the tumorigenesis of glioma, which may serve as a useful prognostic biomarker and potential therapeutic target for glioma.

Xu H, Yao F
Microarray-Based Gene Expression Analysis Identifies Potential Diagnostic and Prognostic Biomarkers for Waldenström Macroglobulinemia.
Acta Haematol. 2018; 140(2):87-96 [PubMed] Related Publications
Waldenström macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is rare but a clinicopathologically distinct B-cell malignancy. This study assessed differentially expressed genes (DEGs) to identify potential WM biomarkers and uncover the underlying the molecular mechanisms of WM progression using gene expression profiles from the Gene Expression Omnibus database. DEGs were identified using the LIMMA package and their potential functions were then analyzed by using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and the protein-protein interaction (PPI) network analysis by using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Data showed that among 1,756 DEGs, 926 were upregulated and 830 were downregulated by comparing WM BM CD19+ with normal PB CD19+ B cell samples, whereas 241 DEGs (95 upregulated and 146 downregulated) were identified by comparing WM BM CD138+ with normal BM CD138+ plasma cell samples. The DEGs were enriched in different GO terms and pathways, including the apoptotic process, cell cycle arrest, immune response, cell adhesion, mitogen-activated protein kinase signaling pathway, toll-like receptor signaling pathway, and the gonadotropin-releasing hormone signaling pathway. Hub nodes in the PPI network included CDK1, JUN, CREBBP, EP300, CAD, CDK2, and MAPK14. Bioinformatics analysis of the GSE9656 dataset identified 7 hub genes that might play an important role in WM development and progression. Some of the candidate genes and pathways may serve as promising therapeutic targets for WM.

Hu S, Liao Y, Chen L
Identification of Key Pathways and Genes in Anaplastic Thyroid Carcinoma via Integrated Bioinformatics Analysis.
Med Sci Monit. 2018; 24:6438-6448 [PubMed] Article available free on PMC after 22/10/2019 Related Publications
BACKGROUND To provide a better understanding of anaplastic thyroid carcinoma (ATC) at the molecular level, this study aimed to identify the genes and key pathways associated with ATC by using integrated bioinformatics analysis. MATERIAL AND METHODS Based on the microarray data GSE9115, GSE65144, and GSE53072 derived from the Gene Expression Omnibus, the differentially expressed genes (DEGs) between ATC samples and normal controls were identified. With DEGs, we performed a series of functional enrichment analyses. Then, a protein-protein interaction (PPI) network was constructed and visualized, with which the hub gene nodes were screened out. Finally, modules analysis for the PPI network was performed to further investigate the potential relationships between DEGs and ATC. RESULTS A total of 537 common DEGs were screened out from all 3 datasets, among which 247 genes were upregulated and 275 genes were downregulated. GO analysis indicated that upregulated DEGs were mainly involved in cell division and mitotic nuclear division and the downregulated DEGs were significantly enriched in ventricular cardiac muscle cell action potential. KEGG pathway analysis showed that the upregulated DEGs were mainly enriched in cell cycle and ECM-receptor interaction and the downregulated DEGs were mainly enriched in thyroid hormone synthesis, insulin resistance, and pathways in cancer. The top 10 hub genes in the constructed PPI network were CDK1, CCNB1, TOP2A, AURKB, CCNA2, BUB1, AURKA, CDC20, MAD2L1, and BUB1B. The modules analysis showed that genes in the top 2 significant modules of PPI network were mainly associated with mitotic cell cycle and positive regulation of mitosis, respectively. CONCLUSIONS We identified a series of key genes along with the pathways that were most closely related with ATC initiation and progression. Our results provide a more detailed molecular mechanism for the development of ATC, shedding light on the potential biomarkers and therapeutic targets.

Kalimutho M, Sinha D, Jeffery J, et al.
CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer.
EMBO Mol Med. 2018; 10(9) [PubMed] Article available free on PMC after 22/10/2019 Related Publications
The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase-dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2-MYC axis. Blocking MEK1/2-PLK1 signaling therefore reduced outgrowth of basal-like syngeneic and human breast tumors in

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