Gene Summary

Gene:CDK2; cyclin dependent kinase 2
Aliases: CDKN2, p33(CDK2)
Summary:This gene encodes a member of a family of serine/threonine protein kinases that participate in cell cycle regulation. The encoded protein is the catalytic subunit of the cyclin-dependent protein kinase complex, which regulates progression through the cell cycle. Activity of this protein is especially critical during the G1 to S phase transition. This protein associates with and regulated by other subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A), and p27Kip1 (CDKN1B). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase 2
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.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: CDK2 (cancer-related)

Yang Q, Wang R, Wei B, et al.
Gene and microRNA Signatures Are Associated with the Development and Survival of Glioblastoma Patients.
DNA Cell Biol. 2019; 38(7):688-699 [PubMed] Related Publications
This study was aimed to identify hub genes associated with the development of glioblastoma (GBM) by conducting a bioinformatic analysis. The raw gene expression data were downloaded from the Gene Expression Omnibus database and The Cancer Genome Atlas project. After the differentially expressed genes (DEGs) were identified, the functional enrichment analysis of DEGs was conducted. Subsequently, the protein-protein interaction (PPI) network, molecular complex detection clusters, and transcriptional factor (TF)-miRNA-target regulatory network were constructed, respectively. Furthermore, the survival analysis of prognostic outcomes and genes was analyzed. In addition, the expression of key genes was validated by quantitative real-time PCR (qRT-PCR) analysis. A total of 884 DEGs, including 418 upregulated and downregulated genes, were identified between GBM and normal samples. The PPI network comprised a set of 3418 pairs involving 751 nodes, and

Tak J, Sabarwal A, Shyanti RK, Singh RP
Berberine enhances posttranslational protein stability of p21/cip1 in breast cancer cells via down-regulation of Akt.
Mol Cell Biochem. 2019; 458(1-2):49-59 [PubMed] Related Publications
Berberine has shown anticancer properties and has potential for a chemopreventive and/or chemotherapeutic agent for breast cancer. Berberine showed cytotoxicity to breast cancer cells, with an increase in the levels of p21/cip1 and p27/kip1, cyclin-dependent kinase inhibitors (CDKI), but mechanisms involved in up-regulating these molecules are largely unknown. Herein, we studied the key regulatory mechanisms involved in berberine-mediated up-regulation of p21/cip1 and p27/kip1. Berberine treatment for 24 and 48 h decreased the number of cells by 44-84% (P < 0.0001) and 38-78% (P < 0.0001), and increased cell death by 12-17% (P < 0.005) and 38-78% (P < 0.0001) in MCF-7 and MDA-MB-231 cells, respectively. Cells were arrested in G1 phase by berberine which was accompanied with up-regulation of mRNA and protein level of both p21/cip1 and p27/kip1. Berberine decreased the expression of protein levels of cyclin D1, cyclin E, CDK2, CDK4, and CDK6 to cause G1 phase arrest. Berberine caused nuclear localization of p21/cip1 in both the cell lines. Our data for the first time showed that the post-translational stability of both the proteins was strongly increased by berberine as examined by cycloheximide chase assay. Inhibition of Akt was associated with berberine-mediated up-regulation of p21/cip1 and also led to a decrease in cell viability accompanied with significant G1 phase cell cycle arrest. Our study revealed that berberine not only up-regulates mRNA and protein levels of p21/cip1 and p27/kip1 but also increases their nuclear localization and post-translational protein stability. Further, Akt inhibition was found to mediate berberine-mediated up-regulation of p21/cip1 but not the p27/kip1.

Shen Z, Liao X, Shao Z, et al.
Short-term stimulation with histone deacetylase inhibitor trichostatin a induces epithelial-mesenchymal transition in nasopharyngeal carcinoma cells without increasing cell invasion ability.
BMC Cancer. 2019; 19(1):262 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT) may be one of the reasons for the failure in some clinical trials regarding histone deacetylase inhibitors (HDACIs)-treated solid tumors. We investigated the effects of a pan-HDACI trichostatin A (TSA) on the proliferation and EMT of nasopharyngeal carcinoma (NPC) cells.
METHODS: Poorly-differentiated NPC cell line CNE2 and undifferentiated C666-1 were treated with various concentrations of TSA, the cell viability was assessed by CCK-8 assay, the morphology was photographed, and the mRNA level of HDACs was assessed by semiquantitative PCR. After determination the cell cycle distributions, cells were subjected to western blotting analysis of cell cycle and EMT-associated genes expression. And the changes in migration ability were assessed by transwell migration assay and scratch wound healing assay. Finally, histone deacetylases activator ITSA-1 was used to assess the reverse of TSA-induced changes in NPC cells.
RESULTS: TSA inhibited the proliferation of CNE2 and C666-1 cells in a concentration-dependent manner and arrested the cell cycle at G1 phases. TSA reduced PCNA, cyclin D1, cyclin E1, CDK2, p16 and p21 expressions and stimulated CDK6 levels. TSA stimulation for 48 h could effectively induce the EMT in CNE2 and C666-1 cells, which showed an increase of spindle-like cells and promoted expression of Vimentin and Snail1 expression in a concentration-dependent manner. Surprisingly, this short period of TSA treatment that induced EMT also impeded the migration ability of CNE2 and C666-1 cells. Interestingly, ITSA-1 rescued TSA-impeded CNE2 and C666-1 cells' proliferation, migration and HDACs expression, also re-induced the cells to turn into epithelial cell phenotypes.
CONCLUSIONS: These results indicate that short-term stimulation of TSA effectively inhibits cell proliferation and induce EMT-like changes in NPC cells but not increase its invasion ability.

Gurung SK, Dana S, Mandal K, et al.
Downregulation of c-Myc and p21 expression and induction of S phase arrest by naphthalene diimide derivative in gastric adenocarcinoma cells.
Chem Biol Interact. 2019; 304:106-123 [PubMed] Related Publications
Naphthalene diimide (NDI) derivatives have been shown to exhibit promising antineoplastic properties. In the current study, we assessed the anticancer and anti-bacterial properties of di-substituted NDI derivative. The naphthalene-bis-hydrazimide, 1, negatively affected the cell viability of three cancer cell lines (AGS, HeLa and PC3) and induced S phase cell cycle arrest along with SubG0/G1 accumulation. Amongst three cell lines, gastric cancer cell line, AGS, showed the highest sensitivity towards the NDI derivative 1. Compound 1 induced extensive DNA double strand breaks causing p53 activation leading to transcription of p53 target gene p21 in AGS cells. Reduction in protein levels of p21 and BRCA1 suggested that 1 treated AGS cells underwent cell death due to accumulation of DNA damage as a result of impaired DNA damage repair. β-catenin downregulation and consequently decrease in levels of c-Myc may have led to 1 induced AGS cell proliferation inhibition.1 induced AGS cell S phase arrest was mediated through CylinA/CDK2 downregulation. The possible mechanisms involved in anticancer activity of 1 includes ROS upregulation, induction of DNA damage, disruption of mitochondrial membrane potential causing ATP depletion, inhibition of cell proliferation and downregulation of antiapoptotic factors ultimately leading to mitochondria mediated apoptosis. Further compound 1 also inhibited H. pylori proliferation as well as H. pylori induced morphological changes in AGS cells. These findings suggest that NDI derivative 1 exhibits two-pronged anticancer activity, one by directly inhibiting cancer cell growth and inducing apoptosis and the other by inhibiting H. pylori.

Xing Y, Ren S, Ai L, et al.
ZNF692 promotes colon adenocarcinoma cell growth and metastasis by activating the PI3K/AKT pathway.
Int J Oncol. 2019; 54(5):1691-1703 [PubMed] Free Access to Full Article Related Publications
Despite considerable recent advancements in colorectal cancer (CRC) therapy, the prognosis of patients with advanced disease remains poor. Further understanding of the molecular mechanisms and treatment strategies of this disease is required. Zinc finger protein 692 (ZNF692), also known as AREBP and Zfp692, was first reported to have an important role in gluconeogenesis. A recent study demonstrated that ZNF692 is overexpressed in lung adenocarcinoma (LUAD) tissues and that ZNF692 knockdown inhibited LUAD cell proliferation, migration, and invasion both in vitro and in vivo. However, the role of ZNF692 in colon adenocarcinoma (COAD) remains unclear. The present study revealed that ZNF692 was upregulated in COAD tissues and cells and that high ZNF692 expression was significantly correlated with lymph node metastasis, distant metastasis and tumor stage in COAD patients. Gain‑ and loss‑of‑function experiments were employed to identify the function of ZNF692 in COAD progression. In vitro and in vivo assays revealed that ZNF692 promoted COAD cell proliferation, migration and invasion. Furthermore, western blot analysis demonstrated that the effects of ZNF692 were mediated by upregulating cyclin D1, cyclin‑dependent kinase 2 (CDK2) and matrix metalloproteinase‑9 (MMP‑9) and by downregulating p27Kip1 through the phosphoinositide 3‑kinase/AKT signaling pathway. Collectively, these data indicated that ZNF692 may serve as a novel oncogene and a potential treatment target in COAD patients.

Chen YN, Ren CC, Yang L, et al.
MicroRNA let‑7d‑5p rescues ovarian cancer cell apoptosis and restores chemosensitivity by regulating the p53 signaling pathway via HMGA1.
Int J Oncol. 2019; 54(5):1771-1784 [PubMed] Related Publications
Ovarian cancer (OC) is the gynecological malignancy type with the highest mortality rate in females. The regulatory effect of microRNAs (miRs) on their target genes serves a key role in tumor development. Therefore, in the present study, whether miR let‑7d‑5p targeting high mobility group A1 (HMGA1) regulated biological characteristics and chemosensitivity of OC cells by mediating the p53 signaling pathway was investigated. The let‑7d‑5p level was detected in OC tissues and adjacent normal tissues, followed by detection in OC cell lines SKOV3, A2780, OVCAR‑3 and CaOV3, and human normal ovarian epithelial cell line (IOSE‑80), in order to select the OC cell line for the following experiments. Subsequently, OC cells were treated with the let‑7d‑5p mimic, siHMGA1 and Tenovin‑1. The targeting association between let‑7d‑5p and HMGA1 was then examined, and the OC cell viability, migration, cycle and apoptosis were evaluated. Subsequently, the chemosensitivity of OC cells to cisplatin was verified. Finally, expression levels of let‑7d‑5p, HMGA1, p21, B‑cell lymphoma‑2 (Bcl‑2)‑associated X (Bax), p27, p53 wild‑type (p53wt), p53 mutated (p53mut), proliferating cell nuclear antigen (PCNA), cyclin‑dependent kinase 2 (CDK2), matrix metallopeptidase (MMP)2, MMP9 and Bcl‑2 were determined. As demonstrated in the results, let‑7d‑5p expression was low in OC tissues and had an increased reduction in the OVCAR‑3 cell line. HMGA1 was confirmed as a target of let‑7d‑5p, and its expression was also silenced by let‑7d‑5p. let‑7d‑5p repressed OC cell viability, migration, cell cycle progression and apoptosis, while it promoted the chemosensitivity of OC cells to cisplatin by targeting HMGA1. The expression of let‑7d‑5p, p21, Bax, p27 and p53wt was increased, while that of HMGA1, p53mut, PCNA, CDK2, MMP2, MMP9 and Bcl‑2 was reduced following cell transfection. The results in the present study provided evidence that let‑7d‑5p may suppress proliferation, and facilitate apoptosis and cisplatin chemosensitivity of OC cells by silencing HMGA1 via the p53 signaling pathway.

Wu B, Wang H, Zhang L, et al.
High expression of RAD18 in glioma induces radiotherapy resistance via down-regulating P53 expression.
Biomed Pharmacother. 2019; 112:108555 [PubMed] Related Publications
As a key regulator of DNA translesion synthesis (TLS) pathway, RAD18 is reported to be abnormally expressed in many kinds of cancers. In glioma, RAD18 was overexpressed in the primary and recurrent glioblastoma multiforme specimens, and its overexpression weakened ionizing radiation-induced apoptosis in glioma A172 cells. Moreover, A172 cells with mutational P53 also showed enhanced radiation resistance. And RAD18 activation induced by cyclin-dependent kinase 2 (CDK2) was repressed by P53. However, whether P53 involves in RAD18-induced radiation resistance remains unknown. Therefore, this study was conducted to explore the effects and mechanism of RAD18 in the radiation resistance of glioma and study P53 role in this process. Results showed that, RAD18 expression was obviously elevated in glioma tissues and cell lines such as U251, SHG-44, A172, U-87 MG and U-118 MG as compared with the normal brain tissues and neuroglia cells. Up-regulation of RAD18 in U-118 MG and A172 cells with lentivirus infection significantly increased cell growth and inhibited cell apoptosis, determined by CCK-8 and flow cytometry technologies. Besides, RAD18 overexpression enhanced cell growth and inhibited cell apoptosis after U-118 MG or A172 cells were irradiated at a dose of 4 Gy. On the contrary, silencing of endogenous RAD18 sensitized U-118 MG and A172 cells to radiation. Moreover, RAD18 and P53 proteins were co-located in the nucleus, and up-regulation of RAD18 decreased the expression of P53 protein and facilitated its nuclear export. Furthermore, cell growth promotion and cell apoptosis inhibition induced by RAD18 up-regulation were impaired when P53 expression was up-regulated under radiation condition. In a word, this study clarifies that RAD18 functions as a promoter in glioma progression and reduces glioma cells' sensibility to radiation through down-regulating P53, which provides new strategies to overcome the radiation resistance in glioma.

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.

Xu C, Zheng J
siRNA against TSG101 reduces proliferation and induces G0/G1 arrest in renal cell carcinoma - involvement of c-myc, cyclin E1, and CDK2.
Cell Mol Biol Lett. 2019; 24:7 [PubMed] Free Access to Full Article Related Publications
Objective: The tumor susceptibility gene 101 (TSG101) is closely associated with various tumor types, but its role in the pathogenesis of renal cell carcinoma (RCC) is still unknown. This study used RNA interference to silence the expression of TSG101 in RCC cell lines and explore the role of TSG101 in RCC.
Methods: Immunohistochemistry and western blot were performed to detect the expression of TSG101 in 15 paired renal tumor samples. A small interfering RNA (siRNA) targeting TSG101 was transfected into A498 and 786-O cell lines. The Cell Counting Kit-8 (CCK-8) assay and colony formation assay were used to observe the changes in cell proliferation after transfection. Flow cytometry was used to detect the effect on the cell cycle. Western blot was conducted to study the changes of related functional proteins.
Results: The expression of TSG101 was higher in RCC tissues than in adjacent normal tissues. The CCK-8 assay showed that the proliferation and colony formation of the A498 and 786-O cell lines were attenuated after suppression of TSG101. Flow cytometry showed that silencing of TSG101 induced G0/G1 arrest. The western blot results revealed that the levels of cell cycle-related proteins (c-myc, cyclin E1 and cyclin-dependent kinase 2 (CDK2)) were markedly decreased in the siRNA groups.
Conclusions: TSG101 promotes proliferation of RCC cells. This positive effect on tumor growth involves activation of c-myc and cyclin E1/CDK2 and their effect on cell cycle distribution.

Deng Z, Chai J, Zeng Q, et al.
The anticancer properties and mechanism of action of tablysin-15, the RGD-containing disintegrin, in breast cancer cells.
Int J Biol Macromol. 2019; 129:1155-1167 [PubMed] Related Publications

Wang X, Huo B, Liu J, et al.
Hepatitis B virus X reduces hepatocyte apoptosis and promotes cell cycle progression through the Akt/mTOR pathway in vivo.
Gene. 2019; 691:87-95 [PubMed] Related Publications
Hepatitis B virus X (HBx), a viral onco-protein encoded by HBV, can promote oncogenesis of HCC. However, the mechanism of HBx in hepatocarcinogenesis is still unclear. In this study, we establish a new mouse model with normal immune system to investigate the role of HBx and its functional mechanisms under normal immune function. The animal model was established by injecting HBx-EGFP-14-19 cells into the hepatic portal vein of KM mice. To verify the mouse model, the expression of HBx in the liver tissue of mice was detected by qRT-PCR, western blotting and immunohistochemistry. The apoptosis index was calculated using the terminal deoxynucleotidyl transferase-dUTP nick-end labeling (TUNEL) assay, and the expression levels of apoptosis-related and cell cycle-related factors were measured. Moreover, expression of proteins in the protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling pathway was detected in HBx-EGFP-14-19 mice with and without use of an Akt inhibitor. The results showed the HBx was successfully overexpressed in liver of KM mice. After overexpressing HBx, the apoptosis index was downregulated in HBx-EGFP-14-19 liver tissue, and the expression levels of caspase-9 and Bad were reduced, but Bcl-xl was increased in HBx-EGFP-14-19 liver tissue. Overexpression of HBx increased the expression of the cyclin-dependent kinase 2 (CDK2), cyclinD1 and cyclinE. Moreover, compared with the low-level HBx group, p-Akt and p-mTOR were increased in the livers of mice with high levels of HBx. However, inactivation of apoptosis by overexpression of HBx was abolished by the treatment with an Akt inhibitor. These results indicate that HBx can induce anti-apoptosis mechanisms in hepatocytes in vivo, which is mediated by the Akt/mTOR signaling pathway.

Zhang Z, Liu X, Xu H, et al.
LINC01170 promotes the progression of endometrial carcinoma by activating the AKT pathway.
J BUON. 2018 Nov-Dec; 23(6):1745-1752 [PubMed] Related Publications
PURPOSE: To investigate the function of LINC01170 in the progression of endometrial carcinoma and its underlying mechanism.
METHODS: The expression profiles and prognostic data of endometrial carcinoma were downloaded by GDC (genomic data commons) analysis tools. Differentially expressed long noncoding (lnc)RNAs were analyzed by the edgeR (empirical analysis of digital gene expression data in R) package. LncRNAs that were related to prognosis of endometrial carcinoma were calculated by the survival function. Moreover, the PHEAT map package was introduced to edit heatmaps of differentially expressed lncRNAs. Human endometrial carcinoma cell lines (Ishikawa, ECC and HEC-IA) were cultured. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expressions of lncRNAs and related genes. Cell proliferation was detected by MTT, and cell cycle and apoptosis were detected by flow cytometry. Additionally, Western blot was used to detect protein expressions of relative genes.
RESULTS: Results showed that LINC01170 was a non-coding RNA. LINC01170 was overexpressed in endometrial carcinoma, which was a risk factor for prognosis of this disease. LINC01170 expressions in carcinoma and para-cancerous tissues of 50 patients with endometrial carcinoma were detected by qRT-PCR and found that the expression level of LINC01170 in endometrial carcinoma was remarkably increased than that of para-cancerous tissues. Moreover, the expression level of LINC01170 in advanced endometrial carcinoma was remarkably higher than that of early-stage disease. After interfering with LINC01170, the proliferation of both the Ishikawa and HEC-1A cells were remarkably decreased, and cell cycle was arrested at the G0/G1 phase. Meanwhile, apoptosis results showed a remarkable apoptosis rate after interfering with LINC01170. Western blot results also demonstrated the decreased activity of AKT pathway and phosphorylated expression of AKT protein after LINC01170 knockdown. In addition, expressions of CDK2, CDK4 and Bcl-2 were decreased after LINC01170 knockdown.
CONCLUSIONS: LINC01170 promotes the progression of endometrial carcinoma through stimulating proliferation, cell cycle transition and inhibiting apoptosis of endometrial carcinoma cells via AKT pathway.

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

Zhu B, Pan Y, Zheng X, et al.
A clinical, biologic and mechanistic analysis of the role of ZNF692 in cervical cancer.
Gynecol Oncol. 2019; 152(2):396-407 [PubMed] Related Publications
OBJECTIVE: Cervical cancer (CC) is the most common malignancy in women. The zinc finger protein 692 (ZNF692) has been identified as a transcription factor and its aberrant expression participates in tumorigenesis of various cancers. However, its biological function and molecular mechanisms in cervical cancer remain unclear.
METHODS: Microarrays were analysed by immunohistochemistry (IHC) to investigate the expression of ZNF692 in cervical cancer and its relationship with clinicopathologic characteristics. siRNAs and expression plasmids were used to reveal the biological function of ZNF692 in CC and subcutaneous xenograft model to examine the role of ZNF692 in vivo. Chromatin Immunoprecipitation and luciferase reporter assay were performed to ascertain whether ZNF692 binds to the promoter region of p27
RESULTS: By analyzing The Cancer Genome Atlas (TCGA) dataset, we confirmed ZNF692 as a potential oncogene in CC. ZNF692 expression was up-regulated in CC tissues compared with that in adjacent normal tissues, and its overexpression was correlated with poor clinicopathologic characteristics. Moreover, ZNF692 promoted the proliferation, migration and invasion of CC cells both in vitro and in vivo. Regarding molecular mechanisms, up-regulation of ZNF692 was found to enhance the G1/S transition via regulating the p27
CONCLUSION: ZNF692 promotes CC cells proliferation and invasion through suppressing p27

Lin YH, Wu MH, Huang YH, et al.
Thyroid hormone negatively regulates tumorigenesis through suppression of BC200.
Endocr Relat Cancer. 2018; 25(12):967-979 [PubMed] Related Publications
Thyroid hormone (T3) and its receptor (TR) are involved in cancer progression. While deregulation of long non-coding RNA (lncRNA) expression has been detected in many tumor types, the mechanisms underlying specific involvement of lncRNAs in tumorigenicity remain unclear. Experiments from the current study revealed negative regulation of BC200 expression by T3/TR. BC200 was highly expressed in hepatocellular carcinoma (HCC) and effective as an independent prognostic marker. BC200 promoted cell growth and tumor sphere formation, which was mediated via regulation of cell cycle-related genes and stemness markers. Moreover, BC200 protected cyclin E2 mRNA from degradation. Cell growth ability was repressed by T3, but partially enhanced upon BC200 overexpression. Mechanistically, BC200 directly interacted with cyclin E2 and promoted CDK2-cyclin E2 complex formation. Upregulation of cell cycle-related genes in hepatoma samples was positively correlated with BC200 expression. Our collective findings support the utility of a potential therapeutic strategy involving targeting of BC200 for the treatment of HCC.

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.

Wang X, Zhang L, Wang W, et al.
Rhotekin 2 silencing inhibits proliferation and induces apoptosis in human osteosarcoma cells.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Human osteosarcoma is the most frequent primary malignant of bone, and often occurs in adolescents. However, molecular mechanism of this disease remains unclear. In the present study, we found that the level of Rhotekin 2 (RTKN2) was up-regulated in osteosarcoma tissues and cell lines. In addition, silencing of RTKN2 of human osteosarcoma cell lines U2OS, inhibited proliferation, and induced G

Li X, Wang H, Ding J, et al.
Celastrol strongly inhibits proliferation, migration and cancer stem cell properties through suppression of Pin1 in ovarian cancer cells.
Eur J Pharmacol. 2019; 842:146-156 [PubMed] Related Publications
Ovarian cancer is one of the most serious diseases worldwide and the fifth-most common cancer among women. Celastrol, extracted from Thunder God Vine, exerts anti-cancer effects on various cancers; however, the mechanism underlying these anti-cancer effects in ovarian cancer needs further investigation. Herein, we investigated the anti-cancer efficacy of celastrol and its underlying mechanism in human ovarian cancer cell lines A2780, OVCAR3, and SKOV3. Celastrol significantly suppressed cell proliferation and migration in a dose-dependent manner. Celastrol resulted in a G2/M cell cycle arrest, accompanied with the down-regulation of Cyclin D1, CDK2, and CDK4. Celastrol induced apoptosis primarily via up-regulation of caspase-3, caspase-8, and Bax, and down-regulation of Bcl-2. Celastrol treatment inhibited the expression of stem cell marker CD44, Nanog, Klf4, and Oct4, and reduced a portion of the CD44

Wei CY, Zhu MX, Lu NH, et al.
Bioinformatics-based analysis reveals elevated MFSD12 as a key promoter of cell proliferation and a potential therapeutic target in melanoma.
Oncogene. 2019; 38(11):1876-1891 [PubMed] Free Access to Full Article Related Publications
Although recent therapeutic advances based on our understanding of molecular phenomena have prolonged the survival of melanoma patients, the prognosis of melanoma remains dismal and further understanding of the underlying mechanism of melanoma progression is needed. In this study, differential expression analyses revealed that many genes, including AKT1 and CDK2, play important roles in melanoma. Functional analyses of differentially expressed genes (DEGs), obtained from the GEO (Gene Expression Omnibus) database, indicated that high proliferative and metastatic abilities are the main characteristics of melanoma and that the PI3K and MAPK pathways play essential roles in melanoma progression. Among these DEGs, major facilitator superfamily domain-containing 12 (MFSD12) was found to have significantly and specifically upregulated expression in melanoma, and elevated MFSD12 level promoted cell proliferation by promoting cell cycle progression. Mechanistically, MFSD12 upregulation was found to activate PI3K signaling, and a PI3K inhibitor reversed the increase in cell proliferation endowed by MFSD12 upregulation. Clinically, high MFSD12 expression was positively associated with shorter overall survival (OS) and disease-free survival (DFS) in melanoma patients, and MFSD12 was an independent prognostic factor for OS and DFS in melanoma patients. Therapeutically, in vivo assays further confirmed that MFSD12 interference inhibited tumor growth and lung metastasis in melanoma. In conclusion, elevated MFSD12 expression promotes melanoma cell proliferation, and MFSD12 is a valuable prognostic biomarker and promising therapeutic target in melanoma.

Wang D, Xu Y, Feng L, et al.
RGS5 decreases the proliferation of human ovarian carcinoma‑derived primary endothelial cells through the MAPK/ERK signaling pathway in hypoxia.
Oncol Rep. 2019; 41(1):165-177 [PubMed] Free Access to Full Article Related Publications
Regulator of G‑protein signaling 5 (RGS5), a tissue‑specific signal‑regulating molecule, plays a key role in the development of the vasculature. It was recently found that RGS5 is abundantly expressed in epithelial ovarian cancer (EOC) compared with the normal ovaries. However, the distribution of RGS5 in EOC and its significance require further investigation. The aim of the present study was to investigate the expression of RGS5 in EOC, as well as its association with cancer differentiation, metastasis and clinicopathological parameters. Immunohistochemistry (IHC), western blotting, RT‑PCR, wound‑healing, cell proliferation and flow cytometric assays were the methods used in the present study. RGS5 was highly expressed in the cytoplasm of ovarian carcinoma cells and in microvascular structures. The expression of RGS5 in EOC was negatively associated with peritoneal metastasis (P=0.004), but it was not found to be associated with age, tumor size, clinical stage or lymph node metastasis (P>0.05). EOC patients with high RGS5 expression had a prolonged progression‑free survival (72.34±8.41 vs. 43.56±5.41 months, P<0.001). High expression of RGS5 was correlated with significantly lower microvascular density (MVD) as indicated by the expression of CD34, whereas the opposite was observed in tissues with low RGS5 expression (P<0.05). Hypoxia increased RGS5 expression in ovarian carcinoma‑derived endothelial cells (ODMECs), whereas the proliferative capacity of ODMECs exhibited a significant increase following RNAi‑mediated reduction of RGS5 expression. These data indicated that RGS5 plays a key role in angiogenesis in ovarian carcinoma. In addition, RGS5 downregulated the expression of the downstream proteins CDC25A, CDK2 and cyclin E, which are mediated by the mitogen‑activated protein kinase/extracellular signal‑regulated kinase pathway, causing ODMEC arrest in the G1 phase of the cell cycle under hypoxic conditions. Collectively, our data indicated that RGS5 is crucial for the occurrence and development of ovarian cancer, and that RGS5 and its signaling pathway may serve as anti‑angiogenesis targets for the treatment of ovarian cancer.

Xie B, Zhao Z, Liu Q, et al.
CircRNA has_circ_0078710 acts as the sponge of microRNA-31 involved in hepatocellular carcinoma progression.
Gene. 2019; 683:253-261 [PubMed] Related Publications
Circular RNAs (circRNAs) as new types of endogenous non-coding RNAs have been recently identified important roles in certain types of pathological responses, and in the occurrence and progression of a variety of human malignancies. In the present study, we aimed to evaluate the role of has_circ_0078710, which is back spliced by THBS2 gene in hepatocellular carcinoma (HCC). Expression levels of has_circ_0078710 were tested in both HCC tissue samples and cells using real-time qRT-PCR. Has_circ_0078710 was significantly unregulated in HCC tissues and cells. Moreover, HCC patients with high level of has_circ_0078710 had the advance stage (TNM III-IV). Finally, we constructed an interaction network among circRNA-miRNA-mRNA and we identified miR-31 as the has_circ_0078710-associatedmiRNA. Furthermore, overexpression of has_circ_0078710 in HCC could up-regulate HDAC and CDK2 levels by sponging miR-31, simultaneously mediating the expression of cell cycle components (cyclin A, cyclin D1, CDK4) and negative cell cycle regulator p21. In vitro and in vivo functional studies showed that overexpression of has_circ_0078710 in HepG2, SMMC-7721 cell lines significantly promoted cell proliferation, migration, invasion and tumor growth by inducing the cell cycle progression. In summary, we identified Has_circ_0078710 as a potential HCC biomarker.

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.

Zhang X, Zhao Y, Wang C, et al.
Rhomboid domain-containing protein 1 promotes breast cancer progression by regulating the p-Akt and CDK2 levels.
Cell Commun Signal. 2018; 16(1):65 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Our previous work revealed that rhomboid domain-containing protein 1 (RHBDD1) participates in the modulation of cell growth and apoptosis in colorectal cancer cells. This study aimed to investigate the function of RHBDD1 in regulating breast cancer progression and its underlying molecular basis.
METHODS: Immunohistochemistry was performed to evaluate RHBDD1 expression in 116 breast cancer tissue and 39 adjacent normal tissue and expression of RHBDD1, phospho-Akt (p-Akt) and cyclin-dependent kinase 2 (CDK2) in the same 84 breast cancer specimens. RHBDD1-knock-out cells were established using breast cancer cell lines. In vitro studies were carried out to estimate the function of RHBDD1 in cell proliferation, migration and invasion. Fluorescence microscopy assay and flow cytometric analysis were used to measure apoptosis and cell cycle regulation. RNA sequencing and western blot analysis were used to investigate the molecular mechanisms of RHBDD1.
RESULTS: RHBDD1 was highly up-regulated in breast cancer tissue compared with that in normal tissue and associated with pathological tumor (pT) stage, pathological tumor-node-metastasis (pTNM) stage and estrogen receptor (ER) expression. RHBDD1 up-regulation was associated with poor prognosis in several subtypes of breast cancer. Deletion of RHBDD1 promoted apoptosis and suppressed proliferation, migration and invasion in breast cancer cells. RHBDD1 deletion suppressed Akt activation and decreased CDK2 protein level via proteasome pathway, thus inhibited cell cycle progression and G1/S phase transition. Moreover, the protein level of RHBDD1, p-Akt and CDK2 was significantly positively correlated in breast cancer tissue.
CONCLUSIONS: Our study reveals that RHBDD1 promotes breast cancer progression by regulating p-Akt and CDK2 protein levels, and might be a potential biomarker and prognostic indicator for breast cancer patients.

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.

Luo B, Gu YY, Wang XD, et al.
Identification of potential drugs for diffuse large b-cell lymphoma based on bioinformatics and Connectivity Map database.
Pathol Res Pract. 2018; 214(11):1854-1867 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is the most main subtype in non-Hodgkin lymphoma. After chemotherapy, about 30% of patients with DLBCL develop resistance and relapse. This study was to identify potential therapeutic drugs for DLBCL using the bioinformatics method. The differentially expressed genes (DEGs) between DLBCL and non-cancer samples were downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. The R software package (SubpathwayMiner) was used to perform pathway analysis on DEGs affected by drugs found in the Connectivity Map (CMap) database. Protein-protein interaction (PPI) networks of DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes online database and Cytoscape software. In order to identify potential novel drugs for DLBCL, the DLBCL-related pathways and drug-affected pathways were integrated. The results showed that 1927 DEGs were identified from TCGA and GEO. We found 54 significant pathways of DLBCL using KEGG pathway analysis. By integrating pathways, we identified five overlapping pathways and 47 drugs that affected these pathways. The PPI network analysis results showed that the CDK2 is closely associated with three overlapping pathways (cell cycle, p53 signaling pathway, and small cell lung cancer). The further literature verification results showed that etoposide, rinotecan, methotrexate, resveratrol, and irinotecan have been used as classic clinical drugs for DLBCL. Anisomycin, naproxen, gossypol, vorinostat, emetine, mycophenolic acid and daunorubicin also act on DLBCL. It was found through bioinformatics analysis that paclitaxel in the drug-pathway network can be used as a potential novel drug for DLBCL.

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.

Vinod Prabhu V, Elangovan P, Niranjali Devaraj S, Sakthivel KM
Targeting apoptosis by 1,2-diazole through regulation of EGFR, Bcl-2 and CDK-2 mediated signaling pathway in human non-small cell lung carcinoma A549 cells.
Gene. 2018; 679:352-359 [PubMed] Related Publications
Lung cancer is the leading cause of cancer deaths worldwide and non-small cell lung carcinoma (NSCLC), a heterogeneous class of tumors, represents approximately 85% of all new lung cancer diagnosis. Conventional treatment options have limited efficacy because most cases are in the advanced stage at the time of diagnosis. The present study evaluates the anti-cancer activity of 1,2-diazole (pyrazole), a natural compound from mangrove plant Rhizophora apiculata (R.apiculata) on A549 lung carcinoma cells. In the present study the anti-cancer mechanism of pyrazole, was examined by the expression level of proteins Epidermal growth factor receptor (EGFR), Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2) and Cyclin-dependent kinase-2 (CDK-2) which are commonly associated with the cell signaling pathways that control cell survival and apoptosis, that could facilitate to develop a novel target and effective treatment approach for patients with NSCLC. Pyrazole significantly induced cell cycle arrest and initiated apoptosis through inhibition of downstream components of EGFR tyrosine kinase pathway. Pyrazole disrupts the mitochondrial membrane potential and modulated the protein levels of Bax and Bcl-2 which could probably lead to caspase-3 activation. Furthermore, Pyrazole suppresses the expression of CDK-2 resulting in cell cycle arrest at G1 phase and in the G1-S phase transition. Taken together, the current study provides new insight in to the precise molecular mechanisms responsible for the anti-cancer activity of pyrazole in NSCLC, A549 cells. The study opens an avenue for development of a natural compound as a potential therapeutic agent which could target cell signaling pathways to combat human NSCLC.

Song N, Zhong J, Hu Q, et al.
FGF18 Enhances Migration and the Epithelial-Mesenchymal Transition in Breast Cancer by Regulating Akt/GSK3β/Β-Catenin Signaling.
Cell Physiol Biochem. 2018; 49(3):1019-1032 [PubMed] Related Publications
BACKGROUND/AIMS: Fibroblast growth factors (FGFs) and their high-affinity receptors contribute to autocrine and paracrine growth stimulation in several human malignant tumors, including breast cancer. However, the mechanisms underlying the carcinogenic actions of FGF18 remain unclear.
METHODS: The transcription level of FGF18 under the hypoxic condition was detected with quantitative PCR (qPCR). A wound-healing assay was performed to assess the role of FGF18 in cell migration. A clonogenicity assay was used to determine whether FGF18 silencing affected cell clonogenicity. Western blotting was performed to investigate Akt/GSK3β/β-catenin pathway protein expression. Binding of β-catenin to the target gene promoter was determined by chromatin immunoprecipitation (ChIP) assays.
RESULTS: FGF18 promoted the epithelial-mesenchymal transition (EMT) and migration in breast cancer cells through activation of the Akt/GSK3β/β-catenin pathway. FGF18 increased Akt-Ser473 and -Thr308 phosphorylation, as well as that of GSK3β-Ser9. FGF18 also enhanced the transcription of proliferation-related genes (CDK2, CCND2, Ki67), metastasis-related genes (TGF-β, MMP-2, MMP-9), and EMT markers (Snail-1, Snail-2, N-cadherin, vimentin, TIMP1). β-catenin bound to the target gene promoter on the ChIP assay.
CONCLUSION: FGF18 contributes to the migration and EMT of breast cancer cells following activation of the Akt/GSK3β/β-catenin pathway. FGF18 expression may be a potential prognostic therapeutic marker for breast cancer.

Jin ZQ, Hao J, Yang X, et al.
Higenamine enhances the antitumor effects of cucurbitacin B in breast cancer by inhibiting the interaction of AKT and CDK2.
Oncol Rep. 2018; 40(4):2127-2136 [PubMed] Related Publications
Cucurbitacin B (Cu B), a tetracyclic triterpenoid derived from Trichosanthes kirilowii Maxim, exhibits anticancer effects against various types of tumor. Higenamine, isolated from Radix Aconiti Lateralis Preparata, has been used as a dietary supplement for regulating metabolic function. The present study suggested that higenamine enhances Cu B-induced cytotoxicity in breast cancer cells and in vivo. Network pharmacology analysis was used to identify the possible mechanism of action. Cu B alone inhibited breast cancer cell growth, induced apoptosis, and arrested the cell cycle in the G2/M phase. Cu B combined with higenamine potentiated the cytotoxic effect of Cu B, resulting in the enhanced induction of apoptosis and G2/M arrest. The network pharmacology analysis also found that the major predicted targets of Cu B in breast cancer were AKT, endoplasmic reticulum, farnesyltransferase, CAAX box, α, platelet-derived growth factor receptor α, peroxisome proliferator-activated receptor, RET proto-oncogene, and vascular endothelial growth factor A. The possible targets of higenamine involved in the synergic action were cyclin A2, cyclin-dependent kinase 2 (CDK2), dihydrofolate reductase, and protein kinase CAMP‑activated catalytic subunit α. The associated pathways were summarized by Kyoto Encyclopedia of Genes and Genomes pathway analysis, and it was hypothesized that higenamine may enhance the antitumor effects of Cu B in breast cancer through inhibition of the interaction of AKT and CDK2. The protein expression was assayed by western blot analysis. The combined treatment also resulted in significant inhibition of growth in vivo.

Gu Y, Wang X, Liu H, et al.
SET7/9 promotes hepatocellular carcinoma progression through regulation of E2F1.
Oncol Rep. 2018; 40(4):1863-1874 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. Histone‑lysine N‑methyltransferase SET7/9 is a protein lysine monomethylase that methylates histone H3K4 as well as various non‑histone proteins. Deregulation of SET7/9 is frequently detected in human cancers. However, the role of SET7/9 in HCC development remains unclear. In the present study, upregulation of SET7/9 and E2F transcription factor 1 (E2F1) expression was detected in 68 samples of HCC tissues compared with these levels noted in the paired healthy liver samples. The expression levels of SET7/9 and E2F1 were significantly correlated with pathological stage and tumor size. Subcellular fractionation and co‑immunoprecipitation analyses revealed protein‑protein interaction between SET7/9 and E2F1 in the cytoplasm of HCC cells. Silencing of SET7/9, as well as treatment with 5'‑deoxy‑5'‑methylthioadenosine (MTA), a protein methylation inhibitor, led to reduced E2F1 protein abundance in HCC cells. Using Cell Counting Kit‑8 (CCK‑8) assay, Transwell migration assay and wound healing assay, significantly decreased cell proliferation, migration and invasion were observed in cells exhibiting downregulation of SET7/9 and E2F1 expression, as well as in wild‑type HCC cells treated with MTA. Furthermore, SET7/9 downregulation and MTA treatment resulted in reduced expression of downstream targets of E2F1, including cyclin A2, cyclin E1 and CDK2. In conclusion, the present study revealed an oncogenic function of SET7/9 in HCC and demonstrated that SET7/9 may be responsible for alterations in the proliferative ability, aggressiveness and invasive/metastatic potential of HCC cells through post‑translational regulation of E2F1.

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