Gene Summary

Gene:CDKN1A; cyclin-dependent kinase inhibitor 1A (p21, Cip1)
Aliases: P21, CIP1, SDI1, WAF1, CAP20, CDKN1, MDA-6, p21CIP1
Summary:This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Nov 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase inhibitor 1
Source:NCBIAccessed: 27 February, 2015


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 (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: CDKN1A (cancer-related)

Kim HS, Jung G
Reactive oxygen species increase HEPN1 expression via activation of the XBP1 transcription factor.
FEBS Lett. 2014; 588(23):4413-21 [PubMed] Related Publications
Hepatocellular carcinoma downregulated 1 (HEPN1), a cell growth arrest- and apoptosis-related gene, is suppressed in hepatocellular carcinoma (HCC). However, transcriptional control of HEPN1 has not been characterized. Here, we show that exposure to reactive oxygen species (ROS) leads to upregulation of the mRNA expression of HEPN1 in HCC cell lines. Mechanistically, ROS increase production of an alternately spliced form of X-box binding protein 1 (XBP1s) and XBP1s increases HEPN1 expression by binding to the HEPN1 promoter, thereby acting as a transcriptional activator. Finally, HEPN1 overexpression increases the expression of p53, p21, and Bax, all of which are ROS-upregulated proteins.

Wang C, Chen Z, Ge Q, et al.
Up-regulation of p21(WAF1/CIP1) by miRNAs and its implications in bladder cancer cells.
FEBS Lett. 2014; 588(24):4654-64 [PubMed] Related Publications
We have previously reported that synthetic dsRNA can activate p21 expression by targeting the p21 promoter, thereby suppressing the proliferation of human bladder cancer cells. As complementarity between dsRNA and its target sequences is necessary for RNA activation, miRNAs may also trigger p21 expression through the same mechanism. Here, the expression levels of three miRNAs (miR-370, miR-1180 and miR-1236) decreased in bladder cancer tissues compared to healthy controls and the levels of these mRNAs positively correlated with p21 mRNA levels. The three miRNAs induced nuclear p21 expression through p21-promoter binding. Overexpression of the three miRNAs inhibited the proliferation of bladder cancer cells mainly by regulating p21. Therefore, these miRNAs could be candidates for anti-cancer drugs.

Jarząb A, Grabarska A, Kiełbus M, et al.
Osthole induces apoptosis, suppresses cell-cycle progression and proliferation of cancer cells.
Anticancer Res. 2014; 34(11):6473-80 [PubMed] Related Publications
BACKGROUND: The aim of the present study was to determine the effects of osthole on cell proliferation and viability, cell-cycle progression and induction of apoptosis in human laryngeal cancer RK33 and human medulloblastoma TE671 cell lines.
MATERIALS AND METHODS: Cell viability was measured by means of the MTT method and cell proliferation by the 5-bromo-2-deoxyuridine (BrdU) incorporation assay. Cell-cycle progression was determined by flow cytometry, and induction of apoptosis by release of oligonucleosomes to the cytosol. The gene expression was estimated by a quantitative polymerase chain reaction (qPCR) method. High-performance counter-current chromatography (HPCCC) was applied for isolation of osthole from fruits of Mutellina purpurea.
RESULTS: Osthole decreased proliferation and cell viability of cancer cells in a dose-dependent manner. The tested compound induced apoptosis, increased the cell numbers in G1 and decreased cell number in S/G2 phases of the cell cycle, differentially regulating CDKN1A and TP53 gene expression depending on cancer cell type.
CONCLUSION: Osthole could be considered as a potential compound for cancer therapy and chemoprevention.

Liu H, Shi D, Liu T, et al.
Lentivirus-mediated silencing of SCIN inhibits proliferation of human lung carcinoma cells.
Gene. 2015; 554(1):32-9 [PubMed] Related Publications
SCIN (scinderin) is a calcium-dependent actin severing and capping protein. Homologue in zebrafish has been found to be related with cell death. In the present study, we found that SCIN is highly expressed in human lung cancer specimens. However, the role of SCIN in lung cancer has not yet been determined. To investigate the function of SCIN in lung carcinoma cells, we took advantage of lentivirus-mediated RNA interference (RNAi) to knockdown SCIN expression in two lung carcinoma cell lines A549 and H1299. Silencing of SCIN significantly inhibited the proliferation and colony formation ability of both cell lines in vitro. Moreover, flow cytometry analysis showed that knockdown of SCIN led to G0/G1 phase cell cycle arrest as well as an excess accumulation of cells in the sub-G1 phase. Furthermore, depletion of SCIN resulted in a significant increase in Cyclin B1, p21 and PARP expression, and a little decrease in Cyclin D1 expression. These results suggest that SCIN plays an important role in lung carcinoma cell proliferation, and lentivirus-mediated silencing of SCIN might be a potential therapeutic approach for the treatment of lung cancer.

Ali I, Braun DP
Resveratrol enhances mitomycin C-mediated suppression of human colorectal cancer cell proliferation by up-regulation of p21WAF1/CIP1.
Anticancer Res. 2014; 34(10):5439-46 [PubMed] Related Publications
BACKGROUND/AIM: Studies have shown that natural products could potentially be employed in combination therapies to decrease toxicity to healthy tissues by chemotherapy drugs. No studies however, have investigated the potential modulatory role of resveratrol (RV) on mitomycin C (MMC)-mediated effects on colorectal cancer. The aim of the present study was to investigate the impact of RV on MMC-mediated inhibition of colorectal cancer cell proliferation and to assess the potential mechanisms for such effects.
MATERIALS AND METHODS: Primary cell lines generated from resected colorectal tumor specimens were treated with RV, MMC or RV+MMC and cell proliferation and gene expression analyses were performed.
RESULTS: Suppression of cell proliferation by RV+MMC was significantly greater than individual treatments. RV+MMC synergistically modulated several genes but the up-regulation of p21(WAF1/CIP1) was several-fold greater.
CONCLUSION: The up-regulation of p21(WAF1/CIP1), which inhibits the cell cycle at G0/G1 and G2/M phases, may represent the predominant mechanism for enhancement of MMC-mediated anti-cancer effects by resveratrol.

Jeon BN, Kim MK, Yoon JH, et al.
Two ZNF509 (ZBTB49) isoforms induce cell-cycle arrest by activating transcription of p21/CDKN1A and RB upon exposure to genotoxic stress.
Nucleic Acids Res. 2014; 42(18):11447-61 [PubMed] Related Publications
ZNF509 is unique among POK family proteins in that four isoforms are generated by alternative splicing. Short ZNF509 (ZNF509S1, -S2 and -S3) isoforms contain one or two out of the seven zinc-fingers contained in long ZNF509 (ZNF509L). Here, we investigated the functions of ZNF509 isoforms in response to DNA damage, showing isoforms to be induced by p53. Intriguingly, to inhibit proliferation of HCT116 and HEK293 cells, we found that ZNF509L activates p21/CDKN1A transcription, while ZNF509S1 induces RB. ZNF509L binds to the p21/CDKN1A promoter either alone or by interacting with MIZ-1 to recruit the co-activator p300 to activate p21/CDKN1A transcription. In contrast, ZNF509S1 binds to the distal RB promoter to interact and interfere with the MIZF repressor, resulting in derepression and transcription of RB. Immunohistochemical analysis revealed that ZNF509 is highly expressed in normal epithelial cells, but was completely repressed in tumor tissues of the colon, lung and skin, indicating a possible role as a tumor suppressor.

Hendrayani SF, Al-Khalaf HH, Aboussekhra A
The cytokine IL-6 reactivates breast stromal fibroblasts through transcription factor STAT3-dependent up-regulation of the RNA-binding protein AUF1.
J Biol Chem. 2014; 289(45):30962-76 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
The development and spread of mammary carcinomas require synergetic interplay between tumor cells and their microenvironment through paracrine secretions, which are still not well defined. We have shown here that interleukin-6 (IL-6), either recombinant or secreted from highly invasive breast cancer cells, down-regulates the tumor suppressor proteins p16(INK4A), p21(WAF1), and p53 and activates breast stromal fibroblasts in a paracrine manner. The formation of myofibroblasts requires p16(INK4A) down-regulation and the activation of the JAK2/STAT3 pathway. Indeed, the transcription factor STAT3 positively controls the expression of the three major myofibroblast markers, SDF-1, α-smooth muscle actin (α-SMA), and TGF-β1, and mediates IL-6-related down-regulation of p16(INK4A), p21(WAF1), and p53 as well as the activation of stromal fibroblasts. Importantly, these effects were mediated through STAT3-dependent up-regulation of the mRNA-binding protein AUF1, whose promoter contains three canonical STAT3 binding sites. AUF1 binds the SDF-1, α-SMA, TGF-β1, and IL-6 mRNAs and reduces their turnover. Consequently, specific AUF1 down-regulation inhibits IL-6-dependent activation of breast stromal fibroblasts, whereas AUF1 ectopic expression of p37(AUF1) activated these cells and enhanced their paracrine induction of epithelial-to-mesenchymal transition in breast cancer cells, which shows a non-cell-autonomous oncogenic function of AUF1. Together, these results demonstrate a major role of IL-6 in activating breast stromal fibroblasts through STAT3-dependent AUF1 induction.

Tecleab A, Zhang X, Sebti SM
Ral GTPase down-regulation stabilizes and reactivates p53 to inhibit malignant transformation.
J Biol Chem. 2014; 289(45):31296-309 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
Ral GTPases are critical effectors of Ras, yet the molecular mechanism by which they induce malignant transformation is not well understood. In this study, we found the expression of K-Ras, RalB, and sometimes RalA, but not AKT1/2 and c-Raf, to be required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild-type p53. Down-regulation of K-Ras, RalB, and sometimes RalA increases p53 protein levels and results in a p53-dependent up-regulation of the expression of p21(WAF). K-Ras, RalA, and RalB depletion increases p53 stability as demonstrated by ataxia telangiectasia-mutated kinase activation, increased Ser-15 phosphorylation, and a significant (up to 6-fold) increase in p53 half-life. Furthermore, depletion of K-Ras and RalB inhibits anchorage-independent growth and invasion and interferes with cell cycle progression in a p53-dependent manner. Depletion of RalA inhibits invasion in a p53-dependent manner. Thus, expression of K-Ras and RalB and possibly RalA proteins is critical for maintaining low levels of p53, and down-regulation of these GTPases reactivates p53 by significantly enhancing its stability, and this contributes to suppression of malignant transformation.

Hu X, Feng Y, Zhang D, et al.
A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer.
Cancer Cell. 2014; 26(3):344-57 [PubMed] Article available free on PMC after 08/09/2015 Related Publications
In a genome-wide survey on somatic copy-number alterations (SCNAs) of long noncoding RNA (lncRNA) in 2,394 tumor specimens from 12 cancer types, we found that about 21.8% of lncRNA genes were located in regions with focal SCNAs. By integrating bioinformatics analyses of lncRNA SCNAs and expression with functional screening assays, we identified an oncogene, focally amplified lncRNA on chromosome 1 (FAL1), whose copy number and expression are correlated with outcomes in ovarian cancer. FAL1 associates with the epigenetic repressor BMI1 and regulates its stability in order to modulate the transcription of a number of genes including CDKN1A. The oncogenic activity of FAL1 is partially attributable to its repression of p21. FAL1-specific siRNAs significantly inhibit tumor growth in vivo.

Athie A, Huarte M
FAL1ing inside an amplicon.
Cancer Cell. 2014; 26(3):303-4 [PubMed] Related Publications
Frequently amplified regions of the cancer genome contain well-known oncogenes. In this issue of Cancer Cell, Hu and colleagues discover that FAL1, a long noncoding RNA is encoded in one of these regions. FAL1 acts as an oncogene by stabilizing BMI1, which results in the repression of CDKN1A expression.

Hui KF, Leung YY, Yeung PL, et al.
Combination of SAHA and bortezomib up-regulates CDKN2A and CDKN1A and induces apoptosis of Epstein-Barr virus-positive Wp-restricted Burkitt lymphoma and lymphoblastoid cell lines.
Br J Haematol. 2014; 167(5):639-50 [PubMed] Related Publications
Epstein-Barr virus (EBV) latent proteins exert anti-apoptotic effects on EBV-transformed lymphoid cells by down-regulating BCL2L11 (BIM), CDKN2A (p16(INK4A) ) and CDKN1A (p21(WAF1) ). However, the potential therapeutic effects of targeting these anti-apoptotic mechanisms remain unexplored. Here, we tested both in vitro and in vivo effects of the combination of histone deacetylase (HDAC) and proteasome inhibitors on the apoptosis of six endemic Burkitt lymphoma (BL) lines of different latency patterns (types I and III and Wp-restricted) and three lymphoblastoid cell lines (LCLs). We found that the combination of HDAC and proteasome inhibitors (e.g. SAHA/bortezomib) synergistically induced the killing of Wp-restricted and latency III BL and LCLs but not latency I BL cells. The synergistic killing was due to apoptosis, as evidenced by the high percentage of annexin V positivity and strong cleavage of PARP1 (PARP) and CASP3 (caspase-3). Concomitantly, SAHA/bortezomib up-regulated the expression of CDKN2A and CDKN1A but did not affect the level of BCL2L11 or BHRF1 (viral homologue of BCL2). The apoptotic effects were dependent on reactive oxygen species generation. Furthermore, SAHA/bortezomib suppressed the growth of Wp-restricted BL xenografts in nude mice. This study provides the rationale to test the novel application of SAHA/bortezomib on the treatment of EBV-associated Wp-restricted BL and post-transplant lymphoproliferative disorder.

Zhang J, He L, Geng XF, et al.
Anti-cancer effects of novel doxorubicin prodrug PDOX in MCF-7 breast cancer cells.
J Huazhong Univ Sci Technolog Med Sci. 2014; 34(4):521-8 [PubMed] Related Publications
Ac-Phe-Lys-PABC-DOX (PDOX) is a smart doxorubicin (DOX) prodrug designed to decrease toxicities while maintaining the potent anticancer effects of DOX. This study was aimed at elucidating the effectiveness and toxicities of DOX and PDOX in patient-derived MCF-7 breast cancer cells in vitro. The MCF-7 cells were exposed to both PDOX and DOX, and cytotoxicities, cell cycle and P53/P21 signaling alterations were studied. Abundant cathepsin B was found in the MCF-7 cells, and treatment with PDOX and DOX triggered dose- and time-dependent cytotoxicity and resulted in a significant reduction in cell viability. The IC50 of PDOX and DOX was 3.91 and 0.94 μmol/L, respectively. Both PDOX and DOX caused an up-regulation of the P53/P21-related signal pathway, and PDOX significantly increased expression of P53 and caspase 3, and arrested the cell cycle at the G1/G2 phase. As compared with DOX, PDOX reduced toxicities, and it may have different action mechanisms on breast cancer cells.

Liszka L
Ductal adenocarcinoma of the pancreas usually retained SMAD4 and p53 protein status as well as expression of epithelial-to-mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis.
Pol J Pathol. 2014; 65(2):100-12 [PubMed] Related Publications
There are limited data on the biology of metastatic pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to compare the expression of immunohistochemical markers that may be involved in the development of metastatic disease in primary PDAC and in synchronous liver metastatic tissues. Thirty-two stains (corresponding to proteins encoded by 31 genes: SMAD4, TP53, ACTA2, CDH1, CDKN1A, CLDN1, CLDN4, CLDN7, CTNNB1, EGFR, ERBB2, FN1, KRT19, MAPK1/MAPK3, MAPK14, MKI67, MMP2, MMP9, MUC1 (3 antibodies), MUC5AC, MUC6, MTOR, MYC, NES, PTGS2, RPS6, RPS6KB1, TGFB1, TGFBR1, VIM) were evaluated using tissue microarray of 26 pairs of primary PDACs and their liver metastases. There were no significant differences in expression levels of examined proteins between primary and secondary lesions. In particular, metastatic PDAC retained the primary tumour's SMAD4 protein status in all and p53 protein status in all but one case. This surprising homogeneity also involved expression levels of markers of epithelial-to-mesenchymal transition as well as cell cycle regulators studied. In conclusion, the biological profiles of primary PDACs and their liver metastases seemed to be similar. Molecular alterations of PDAC related to a set of immunohistochemical markers examined in the present study were already present at the stage of localized disease.

Lin K, Farahani M, Yang Y, et al.
Loss of MIR15A and MIR16-1 at 13q14 is associated with increased TP53 mRNA, de-repression of BCL2 and adverse outcome in chronic lymphocytic leukaemia.
Br J Haematol. 2014; 167(3):346-55 [PubMed] Related Publications
This study was conducted to investigate the possibility that TP53 mRNA is variably expressed in chronic lymphocytic leukaemia (CLL) and that under-expression is associated with TP53 dysfunction and adverse outcome. Although TP53 mRNA levels did indeed vary among the 104 CLL samples examined, this variability resulted primarily from over-expression of TP53 mRNA in 18 samples, all of which lacked TP53 deletion/mutation. These patients had higher lymphocyte counts and shorter overall and treatment-free survival times compared to cases with low TP53 mRNA expression and no TP53 deletion/mutation. Furthermore, TP53 mRNA levels did not correlate with levels of TP53 protein or its transcriptional target CDKN1A. We speculated that the adverse outcome associated with TP53 mRNA over-expression might reflect variation in levels of MIR15A and MIR16-1, which are encoded on chromosome 13q14 and target TP53 and some oncogenes including BCL2. In keeping with our hypothesis, 13q14 copy number and levels of MIR15A/MIR16-1 correlated positively with one another but negatively with levels of TP53 mRNA and BCL2 mRNA. Our findings support a model in which loss of MIR15A/MIR16-1 at chromosome 13q14 results in adverse outcome due to de-repression of oncogenes such as BCL2, and up-regulation of TP53 mRNA as a bystander effect.

Gupta R, Dong Y, Solomon PD, et al.
Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A.
Proc Natl Acad Sci U S A. 2014; 111(30):E3062-71 [PubMed] Article available free on PMC after 08/09/2015 Related Publications
Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunction. Here, we show that loss of the p53 target gene cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21(WAF1/CIP1)) increases apoptosis induction following telomerase inhibition in a variety of cancer cell lines and mouse xenografts. This effect is highly specific to p21, as loss of other checkpoint proteins and CDK inhibitors did not affect apoptosis. In telomerase, inhibited cell loss of p21 leads to E2F1- and p53-mediated transcriptional activation of p53-upregulated modulator of apoptosis, resulting in increased apoptosis. Combined genetic or pharmacological inhibition of telomerase and p21 synergistically suppresses tumor growth. Furthermore, we demonstrate that simultaneous inhibition of telomerase and p21 also suppresses growth of tumors containing mutant p53 following pharmacological restoration of p53 activity. Collectively, our results establish that inactivation of p21 leads to increased apoptosis upon telomerase inhibition and thus identify a genetic vulnerability that can be exploited to treat many human cancers containing either wild-type or mutant p53.

Tessoulin B, Descamps G, Moreau P, et al.
PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance.
Blood. 2014; 124(10):1626-36 [PubMed] Related Publications
The aim of this study was to assess the efficiency of p53 reactivation and induction of massive apoptosis (PRIMA-1(Met)) in inducing myeloma cell death, using 27 human myeloma cell lines (HMCLs) and 23 primary samples. Measuring the lethal dose (LD50) of HMCLs revealed that HMCLs displayed heterogeneous sensitivity, with an LD50 ranging from 4 μM to more than 200 μM. The sensitivity of HMCLs did not correlate with myeloma genomic heterogeneity or TP53 status, and PRIMA-1(Met) did not induce or increase expression of the p53 target genes CDKN1A or TNFRSF10B/DR5. However, PRIMA-1(Met) increased expression of NOXA in a p53-independent manner, and NOXA silencing decreased PRIMA1(Met)-induced cell death. PRIMA-1(Met) depleted glutathione (GSH) content and induced reactive oxygen species production. The expression of GSH synthetase correlated with PRIMA-1(Met) LD50 values, and we showed that a GSH decrease mediated by GSH synthetase silencing or by and L-buthionine sulphoximine, an irreversible inhibitor of γ-glutamylcysteine synthetase, increased PRIMA-1(Met)-induced cell death and overcame PRIMA-1(Met) resistance. PRIMA-1(Met) (10 μM) induced cell death in 65% of primary cells independent of the presence of del17p; did not increase DR5 expression, arguing against an activation of p53 pathway; and synergized with L-buthionine sulphoximine in all samples. Finally, we showed in mouse TP53(neg) JJN3-xenograft model that PRIMA-1(Met) inhibited myeloma growth and synergized with L-buthionine sulphoximine in vivo.

Fecteau JF, Corral LG, Ghia EM, et al.
Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21(WAF1/Cip1)-dependent mechanism independent of functional p53.
Blood. 2014; 124(10):1637-44 [PubMed] Article available free on PMC after 04/09/2015 Related Publications
Lenalidomide has demonstrated clinical activity in patients with chronic lymphocytic leukemia (CLL), even though it is not cytotoxic for primary CLL cells in vitro. We examined the direct effect of lenalidomide on CLL-cell proliferation induced by CD154-expressing accessory cells in media containing interleukin-4 and -10. Treatment with lenalidomide significantly inhibited CLL-cell proliferation, an effect that was associated with the p53-independent upregulation of the cyclin-dependent kinase inhibitor, p21(WAF1/Cip1) (p21). Silencing p21 with small interfering RNA impaired the capacity of lenalidomide to inhibit CLL-cell proliferation. Silencing cereblon, a known molecular target of lenalidomide, impaired the capacity of lenalidomide to induce expression of p21, inhibit CD154-induced CLL-cell proliferation, or enhance the degradation of Ikaros family zinc finger proteins 1 and 3. We isolated CLL cells from the blood of patients before and after short-term treatment with low-dose lenalidomide (5 mg per day) and found the leukemia cells were also induced to express p21 in vivo. These results indicate that lenalidomide can directly inhibit proliferation of CLL cells in a cereblon/p21-dependent but p53-independent manner, at concentrations achievable in vivo, potentially contributing to the capacity of this drug to inhibit disease-progression in patients with CLL.

Minami Y, Kohsaka S, Tsuda M, et al.
SS18-SSX-regulated miR-17 promotes tumor growth of synovial sarcoma by inhibiting p21WAF1/CIP1.
Cancer Sci. 2014; 105(9):1152-9 [PubMed] Related Publications
MicroRNA (miRNA) can function as tumor suppressors or oncogenes, and also as potential specific cancer biomarkers; however, there are few published studies on miRNA in synovial sarcomas, and their function remains unclear. We transfected the OncomiR miRNA Precursor Virus Library into synovial sarcoma Fuji cells followed by a colony formation assay to identify miRNAs to confer an aggressive tumorigenicity, and identified miR-17-5p from the large colonies. MiR-17 was found to be induced by a chimeric oncoprotein SS18-SSX specific for synovial sarcoma, and all examined cases of human synovial sarcoma expressed miR-17, even at high levels in several cases. Overexpression of miR-17 in synovial sarcoma cells, Fuji and HS-SYII, increased colony forming ability in addition to cell growth, but not cell motility and invasion. Tumor volume formed in mice in vivo was significantly increased by miR-17 overexpression with a marked increase of MIB-1 index. According to PicTar and Miranda algorithms, which predicted CDKN1A (p21) as a putative target of miR-17, a luciferase assay was performed and revealed that miR-17 directly targets the 3'-UTR of p21 mRNA. Indeed, p21 protein level was remarkably decreased by miR-17 overexpression in a p53-independent manner. It is noteworthy that miR-17 succeeded in suppressing doxorubicin-evoked higher expression of p21 and conferred the drug resistance. Meanwhile, introduction of anti-miR-17 in Fuji and HS-SYII cells significantly decreased cell growth, consistent with rescued expression of p21. Taken together, miR-17 promotes the tumor growth of synovial sarcomas by post-transcriptional suppression of p21, which may be amenable to innovative therapeutic targeting in synovial sarcoma.

Liu X, Tian X, Wang F, et al.
BRG1 promotes chemoresistance of pancreatic cancer cells through crosstalking with Akt signalling.
Eur J Cancer. 2014; 50(13):2251-62 [PubMed] Related Publications
Gemcitabine is a standard chemotherapeutic agent for locally advanced and metastatic pancreatic cancer. However, the chemoresistance of pancreatic cancer is the major barrier to efficient chemotherapy. Here, we reported that BRG1, a chromatin modulator, was exclusively overexpressed in human pancreatic ductal adenocarcinoma tissues. BRG1 knockdown inhibited PANC-1 and MIA PaCa-2 cell growth in vitro and in vivo, reduced the phosphorylation/activation of Akt and p21(cip/waf), enhanced intrinsic and gemcitabine induced apoptosis and attenuated gemcitabine-induced downregulation of E-cadherin. Moreover, by establishing acquired chemoresistance of MIA PaCa-2 cells in vitro, we found that BRG1 knockdown effectively reversed the chemoresistance to gemcitabine. Surprisingly, inhibiting Akt phosphorylation resulted in BRG1 suppression in pancreatic cancer cells, indicating BRG1 as a new downstream target of Akt signalling. Taken together, our findings suggest that BRG1 promotes both intrinsic and acquired chemoresistance of pancreatic cancer cells, and BRG1 crosstalks with Akt signalling to form a positive feedback loop to promote pancreatic cancer development.

Yadav DS, Chattopadhyay I, Verma A, et al.
A pilot study evaluating genetic alterations that drive tobacco- and betel quid-associated oral cancer in Northeast India.
Tumour Biol. 2014; 35(9):9317-30 [PubMed] Related Publications
The susceptibility of an individual to oral cancer is mediated by genetic factors and carcinogen-exposure behaviors such as betel quid chewing, tobacco use, and alcohol consumption. This pilot study was aimed to identify the genetic alteration in 100 bp upstream and downstream flanking regions in addition to the exonic regions of 169 cancer-associated genes by using Next Generation sequencing with aim to elucidate the molecular pathogenesis of tobacco- and betel quid-associated oral cancer of Northeast India. To understand the role of chemical compounds present in tobacco and betel quid associated with the progression of oral cancer, single nucleotide polymorphisms (SNPs) and insertion and deletion (Indels) found in this study were analyzed for their association with chemical compounds found in tobacco and betel quid using Comparative Toxogenomic Database. Genes (AR, BRCA1, IL8, and TP53) with novel SNP were found to be associated with arecoline which is the major component of areca nut. Genes (BARD1, BRCA2, CCND2, IGF1R, MSH6, and RASSF1) with novel deletion and genes (APC, BRMS1, CDK2AP1, CDKN2B, GAS1, IGF1R, and RB1) with novel insertion were found to be associated with aflatoxin B1 which is produced by fermented areca nut. Genes (ADH6, APC, AR, BARD1, BRMS1, CDKN1A, E2F1, FGFR4, FLNC, HRAS, IGF1R, IL12B, IL8, NBL1, STAT5B, and TP53) with novel SNP were found to be associated with aflatoxin B1. Genes (ATM, BRCA1, CDKN1A, EGFR, IL8, and TP53) with novel SNP were found to be associated with tobacco specific nitrosamines.

Wang H, Zhu LJ, Yang YC, et al.
MiR-224 promotes the chemoresistance of human lung adenocarcinoma cells to cisplatin via regulating G₁/S transition and apoptosis by targeting p21(WAF1/CIP1).
Br J Cancer. 2014; 111(2):339-54 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
BACKGROUND: Increasing evidence has shown that microRNAs (miRNAs) can serve as oncogenes and tumour suppressors to participate in tumour development. However, the roles of miRNAs in chemoresistance of human lung adenocarcinoma (LA) remain largely undefined.
METHODS: On the basis of miRNA microarray data, miR-224 was identified as the most upregulated miRNA in cisplatin (DDP; cis-diamminedichloroplatinum II)-resistant A549 cells compared with parental A549 cells. The aim of our study was to investigate the roles of miR-224 in the formation of DDP-resistant phenotype of LA cells and its possible molecular mechanisms.
RESULTS: Here we showed that miR-224 could promote the in vitro and in vivo DDP resistance of LA cells via regulating G1/S cell cycle transition and apoptosis. p21(WAF1/CIP1), a potent cyclin-dependent kinase inhibitor, was identified as the direct and functional target gene of miR-224. Overexpression of p21(WAF1/CIP1) could phenocopy the effect of miR-224 downregulation and silencing of p21(WAF1/CIP1) could partially reverse the effect of miR-224 downregulation on DDP resistance of DDP-resistant LA cells. In addition, miR-224 could affect the G1/S transition of cell cycle and apoptosis in LA cells through the p21(WAF1/CIP1)-pRb pathway and the intrinsic mitochondrial death pathway. Furthermore, miR-224 was found to be downregulated in DDP-responding LA tissues, and its expression was inversely correlated with p21(WAF1/CIP1). Multivariate analyses indicated that the status of miR-224 might be an independent prognostic factor for predicting the survival of LA patients.
CONCLUSIONS: Our findings shed novel light on the roles of miR-224/p21(WAF1/CIP1) signalling in the DDP resistance of LA cells, and targeting it will be a potential strategic approach for reversing the DDP resistance in human LAs.

Wang CM, Liu R, Wang L, et al.
SUMOylation of FOXM1B alters its transcriptional activity on regulation of MiR-200 family and JNK1 in MCF7 human breast cancer cells.
Int J Mol Sci. 2014; 15(6):10233-51 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Transcription factor Forkhead Box Protein M1 (FOXM1) is a well-known master regulator in controlling cell-cycle pathways essential for DNA replication and mitosis, as well as cell proliferation. Among the three major isoforms of FOXM1, FOXM1B is highly associated with tumor growth and metastasis. The activities of FOXM1B are modulated by post-translational modifications (PTMs), such as phosphorylation, but whether it is modified by small ubiquitin-related modifier (SUMO) remains unknown. The aim of the current study was to determine whether FOXM1B is post-translationally modified by SUMO proteins and also to identify SUMOylation of FOXM1B on its target gene transcription activity. Here we report that FOXM1B is clearly defined as a SUMO target protein at the cellular levels. Moreover, a SUMOylation protease, SENP2, significantly decreased SUMOylation of FOXM1B. Notably, FOXM1B is selectively SUMOylated at lysine residue 463. While SUMOylation of FOXM1B is required for full repression of its target genes MiR-200b/c and p21, SUMOylation of FOXM1B is essential for full activation of JNK1 gene. Overall, we provide evidence that FOXM1B is post-translationally modified by SUMO and SUMOylation of FOXM1B plays a functional role in regulation of its target gene activities.

Gallagher SJ, Mijatov B, Gunatilake D, et al.
The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells.
J Invest Dermatol. 2014; 134(11):2795-805 [PubMed] Related Publications
Epigenetic changes are widespread in melanoma and contribute to the pathogenic biology of this disease. In the present study, we show that I-BET151, which belongs to a new class of drugs that target the BET family of epigenetic "reader" proteins, inhibits melanoma growth in vivo and induced variable degrees of apoptosis in a panel of melanoma cells. Apoptosis was caspase dependent and associated with G1 cell cycle arrest. All melanoma cells tested had increased levels of the BH3 proapoptotic protein BIM, which appeared to be regulated by the BRD2 BET protein and to some extent by BRD3. In contrast, knockdown experiments indicated that inhibition of BRD4 was associated with decreased levels of BIM. Apoptosis was dependent on BIM in some but not all cell lines, indicating that other factors were determinants of apoptosis, such as downregulation of antiapoptotic proteins revealed in gene expression arrays. G1 cell cycle arrest appeared to be mediated by p21 and resulted from inhibition of the BRD4 protein. The activity of BET protein inhibitors appears independent of the BRAF and NRAS mutational status of melanoma, and further studies to assess their therapeutic role in melanoma are warranted.

Wang X, Lin C, Zhao X, et al.
Acylglycerol kinase promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1 transcription factor.
Mol Cancer. 2014; 13:106 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
BACKGROUND: Acylglycerol kinase (AGK) is reported to be overexpressed in multiple cancers. The clinical significance and biological role of AGK in breast cancer, however, remain to be established.
METHODS: AGK expression in breast cancer cell lines, paired patient tissues were determined using immunoblotting and Real-time PCR. 203 human breast cancer tissue samples were analyzed by immunochemistry (IHC) to investigate the relationship between AGK expression and the clinicopathological features of breast cancer. Functional assays, such as colony formation, anchorage-independent growth and BrdU assay, and a xenograft tumor model were used to determine the oncogenic role of AGK in human breast cancer progression. The effect of AGK on FOXO1 transactivity was further investigated using the luciferase reporter assays, and by detection of the FOXO1 downstream genes.
RESULTS: Herein, we report that AGK was markedly overexpressed in breast cancer cells and clinical tissues. Immunohistochemical analysis showed that the expression of AGK significantly correlated with patients' clinicopathologic characteristics, including clinical stage and tumor-nodule-metastasis (TNM) classification. Breast cancer patients with higher levels of AGK expression had shorter overall survival compared to patients with lower AGK levels. We gained valuable insights into the mechanism of AGK expression in breast cancer cells by demonstrating that overexpressing AGK significantly enhanced, whereas silencing endogenous AGK inhibited, the proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo. Furthermore, overexpression of AGK enhanced G1-S phase transition in breast cancer cells, which was associated with activation of AKT, suppression of FOXO1 transactivity, downregulation of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 and upregulation of the cell cycle regulator cyclin D1.
CONCLUSIONS: Taken together, these findings provide new evidence that AGK plays an important role in promoting proliferation and tumorigenesis in human breast cancer and may serve as a novel prognostic biomarker and therapeutic target in this disease.

Togashi Y, Sakamoto H, Hayashi H, et al.
Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer.
Mol Cancer. 2014; 13:126 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
BACKGROUND: Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear.
METHODS AND RESULTS: We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21CIP1/WAF1 in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene.
CONCLUSION: We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.

Poos K, Smida J, Nathrath M, et al.
Structuring osteosarcoma knowledge: an osteosarcoma-gene association database based on literature mining and manual annotation.
Database (Oxford). 2014; 2014 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Osteosarcoma (OS) is the most common primary bone cancer exhibiting high genomic instability. This genomic instability affects multiple genes and microRNAs to a varying extent depending on patient and tumor subtype. Massive research is ongoing to identify genes including their gene products and microRNAs that correlate with disease progression and might be used as biomarkers for OS. However, the genomic complexity hampers the identification of reliable biomarkers. Up to now, clinico-pathological factors are the key determinants to guide prognosis and therapeutic treatments. Each day, new studies about OS are published and complicate the acquisition of information to support biomarker discovery and therapeutic improvements. Thus, it is necessary to provide a structured and annotated view on the current OS knowledge that is quick and easily accessible to researchers of the field. Therefore, we developed a publicly available database and Web interface that serves as resource for OS-associated genes and microRNAs. Genes and microRNAs were collected using an automated dictionary-based gene recognition procedure followed by manual review and annotation by experts of the field. In total, 911 genes and 81 microRNAs related to 1331 PubMed abstracts were collected (last update: 29 October 2013). Users can evaluate genes and microRNAs according to their potential prognostic and therapeutic impact, the experimental procedures, the sample types, the biological contexts and microRNA target gene interactions. Additionally, a pathway enrichment analysis of the collected genes highlights different aspects of OS progression. OS requires pathways commonly deregulated in cancer but also features OS-specific alterations like deregulated osteoclast differentiation. To our knowledge, this is the first effort of an OS database containing manual reviewed and annotated up-to-date OS knowledge. It might be a useful resource especially for the bone tumor research community, as specific information about genes or microRNAs is quick and easily accessible. Hence, this platform can support the ongoing OS research and biomarker discovery. Database URL:

Kang KW, Lee MJ, Song JA, et al.
Overexpression of goosecoid homeobox is associated with chemoresistance and poor prognosis in ovarian carcinoma.
Oncol Rep. 2014; 32(1):189-98 [PubMed] Related Publications
Ovarian carcinoma is the most lethal cancer among all gynecological malignancies due to recurrence through chemoresistance. The aim of the present study was to identify new biomarkers to predict chemoresistance and prognosis in ovarian carcinomas. The mRNA expression by qRT-PCR was examined in 60 ovarian serous carcinomas for selected genes from the screening by PCR array focusing on apoptosis, epithelial-to-mesenchymal transition and cancer pathways. The clinical impact was assessed by analyzing the correlation between gene expression and clinicopathological variables. Further validation with immunohistochemistry was performed with 75 cases of serous carcinomas. The chemoresistance was significantly associated with high expression of FOS, GSC, SNAI1, TERT and TNFRSF10D, and low expression of CDKN1A, TNFRSF10A, TNFRSF10C and TRAF1 (p<0.05, t-test). Low expression of TRAF1 and high expression of E2F1, FOS, TERT and GSC were significantly associated with advanced clinical stage (p<0.05, χ2-test). Lymph node metastasis was significantly associated with high expression of GSC. The upregulation group of TERT, GSC, NOTCH1 and SNAI1, and downregulation group of TRAF1 were significantly associated with poor overall survival (p<0.05, log-rank test). On further validation with immunohistochemistry, overexpression of goosecoid homeobox (GSC) was associated with poor overall survival. The results suggest that GSC is the most potential biomarker of drug response and poor prognosis in ovarian serous carcinomas.

Kim JY, Yi BR, Go RE, et al.
Methoxychlor and triclosan stimulates ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an estrogen receptor-dependent pathway.
Environ Toxicol Pharmacol. 2014; 37(3):1264-74 [PubMed] Related Publications
Methoxychlor and triclosan are emergent or suspected endocrine-disrupting chemicals (EDCs). Methoxychlor [MXC; 1,1,1-trichlor-2,2-bis (4-methoxyphenyl) ethane] is an organochlorine pesticide that has been primarily used since dichlorodiphenyltrichloroethane (DDT) was banned. In addition, triclosan (TCS) is used as a common component of soaps, deodorants, toothpastes, and other hygiene products at concentrations up to 0.3%. In the present study, the potential impact of MXC and TCS on ovarian cancer cell growth and underlying mechanism(s) was examined following their treatments in BG-1 ovarian cancer cells. As results, MXC and TCS induced BG-1 cell growth via regulating cyclin D1, p21 and Bax genes related with cell cycle and apoptosis. A methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay confirmed that the proliferation of BG-1 ovarian cancer cells was stimulated by MXC (10(-6), 10(-7), 10(-8), and 10(-9)M) or TCS (10(-6), 10(-7), 10(-8), and 10(-9)M). Treatment of BG-1 cells with MXC or TCS resulted in the upregulation of cyclin D1 and downregulation of p21 and Bax transcriptions. In addition, the protein level of cyclin D1 was increased by MXC or TCS while p21 and Bax protein levels appeared to be reduced in these cells. Furthermore, MXC- or TCS-induced alterations of these genes were reversed in the presence of ICI 182,780 (10(-7)M), suggesting that the changes in these gene expressions may be regulated by an ER-dependent signaling pathway. In conclusion, the results of our investigation indicate that two potential EDCs, MXC and TCS, may stimulate ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an ER-dependent pathway.

Choi WI, Kim MY, Jeon BN, et al.
Role of promyelocytic leukemia zinc finger (PLZF) in cell proliferation and cyclin-dependent kinase inhibitor 1A (p21WAF/CDKN1A) gene repression.
J Biol Chem. 2014; 289(27):18625-40 [PubMed] Article available free on PMC after 04/07/2015 Related Publications
Promyelocytic leukemia zinc finger (PLZF) is a transcription repressor that was initially isolated as a fusion protein with retinoic acid receptor α. PLZF is aberrantly overexpressed in various human solid tumors, such as clear cell renal carcinoma, glioblastoma, and seminoma. PLZF causes cellular transformation of NIH3T3 cells and increases cell proliferation in several cell types. PLZF also increases tumor growth in the mouse xenograft tumor model. PLZF may stimulate cell proliferation by controlling expression of the genes of the p53 pathway (ARF, TP53, and CDKN1A). We found that PLZF can directly repress transcription of CDKN1A encoding p21, a negative regulator of cell cycle progression. PLZF binds to the proximal Sp1-binding GC-box 5/6 and the distal p53-responsive elements of the CDKN1A promoter to repress transcription. Interestingly, PLZF interacts with Sp1 or p53 and competes with Sp1 or p53. PLZF interacts with corepressors, such as mSin3A, NCoR, and SMRT, thereby deacetylates Ac-H3 and Ac-H4 histones at the CDKN1A promoter, which indicated the involvement of the corepressor·HDACs complex in transcription repression by PLZF. Also, PLZF represses transcription of TP53 and also decreases p53 protein stability by ubiquitination. PLZF may act as a potential proto-oncoprotein in various cell types.

Fujitomo T, Daigo Y, Matsuda K, et al.
Identification of a nuclear protein, LRRC42, involved in lung carcinogenesis.
Int J Oncol. 2014; 45(1):147-56 [PubMed] Related Publications
On the basis of the gene expression profiles of 120 lung cancer cases using a cDNA microarray containing 27,648 genes or expressed sequence tags (ESTs), we identified LRRC42 (Leucine-rich repeat containing 42) to be significantly upregulated in the majority of lung cancers. Northern blot analysis demonstrated that LRRC42 was expressed only in testis among normal tissues examined. Knockdown of LRRC42 expression by siRNA against LRRC42 significantly suppressed the growth of lung cancer cells. On the other hand, stable induction of LRRC42 expression significantly promoted cell growth. LRRC42, which was found to localize in the nucleus of mammalian cells, is likely to interact with and stabilize GATAD2B (GATA zinc finger domain-containing 2B) and MBD3 (Methyl-CpG-binding domain protein 3) proteins that could contribute to lung cancer cell proliferation partly through the regulation of p21Waf1/Cip1. Our findings suggest that LRRC42 overexpression as well as its interaction with LRRC42-GATAD2B might play essential roles in lung carcinogenesis, and be a promising molecular target for lung cancer therapy.

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