The deregulated promoter methylation of the<i>Polo-like kinases</i>as a potential biomarker in hematological malignancies

Ward, Alejandra; Sivakumar, Gayathri; Kanjeekal, Sindu M.; Hamm, Caroline; Labute, Brayden C.; Shum, David; Hudson, John W.

doi:10.3109/10428194.2014.971407

Cited by 18 publications

(19 citation statements)

References 49 publications

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“…4 ). In recent studies, methylation of PLK1 57 and genetic mutations of PLK1 58 and TOP2A 59 have been reported in human cancers. Furthermore, we used the genome-wide high-throughput DNA methylation profile of human cervical cancer from TCGA and ESCs 41 to validate our findings.…”

Section: Resultsmentioning

confidence: 99%

Investigating core genetic-and-epigenetic cell cycle networks for stemness and carcinogenic mechanisms, and cancer drug design using big database mining and genome-wide next-generation sequencing data

Chen

2016

Cell Cycle

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Recent studies have demonstrated that cell cycle plays a central role in development and carcinogenesis. Thus, the use of big databases and genome-wide high-throughput data to unravel the genetic and epigenetic mechanisms underlying cell cycle progression in stem cells and cancer cells is a matter of considerable interest.Real genetic-and-epigenetic cell cycle networks (GECNs) of embryonic stem cells (ESCs) and HeLa cancer cells were constructed by applying system modeling, system identification, and big database mining to genome-wide next-generation sequencing data. Real GECNs were then reduced to core GECNs of HeLa cells and ESCs by applying principal genome-wide network projection. In this study, we investigated potential carcinogenic and stemness mechanisms for systems cancer drug design by identifying common core and specific GECNs between HeLa cells and ESCs. Integrating drug database information with the specific GECNs of HeLa cells could lead to identification of multiple drugs for cervical cancer treatment with minimal side-effects on the genes in the common core. We found that dysregulation of miR-29C, miR-34A, miR-98, and miR-215; and methylation of ANKRD1, ARID5B, CDCA2, PIF1, STAMBPL1, TROAP, ZNF165, and HIST1H2AJ in HeLa cells could result in cell proliferation and anti-apoptosis through NFκB, TGF-β, and PI3K pathways. We also identified 3 drugs, methotrexate, quercetin, and mimosine, which repressed the activated cell cycle genes, ARID5B, STK17B, and CCL2, in HeLa cells with minimal side-effects.

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Section: Resultsmentioning

confidence: 99%

Investigating core genetic-and-epigenetic cell cycle networks for stemness and carcinogenic mechanisms, and cancer drug design using big database mining and genome-wide next-generation sequencing data

Chen

2016

Cell Cycle

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“…The analysis in mouse model however showed differential findings in which the hypomethylation was detected in tumour tissues with high PLK1 expression. In addition, the same group also demonstrated the correlation between DNA methylation of the PLK1 promoter region and the PLK1 expression in haematological malignancies [16]. The contradictory results suggest the role of the DNA methylation may be more complicated in determining PLK1 expression.…”

Section: Discussionmentioning

confidence: 94%

“…Mutation of PLK1 gene that had been reported [14] is mainly linked to the lower stability of PLK1 in the cells and the majority of the mutation is not systematically reviewed for the contribution on PLK1 overexpression. DNA methylation of the CpGs in PLK1 promoter regions has also been reported to be associated with the expression of PLK1 in hepatocellular carcinoma [15] and haematological malignancies [16]. Furthermore, the reported link between DNA methylation and irradiation (IR) exposure also makes it an interesting aspect to study [17].…”

Section: Introductionmentioning

confidence: 99%

Exploration of Mutation and DNA Methylation of Polo-Like Kinase 1 (PLK1) in Colorectal Cancer

Shin¹,

Wang²,

Lee³

2017

OJPathology

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Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays critical roles in cell cycling and DNA damage response. Overexpression of PLK1 is associated with the poorer prognosis of cancers, including colorectal cancer (CRC). Although the downstream pathways of the overexpression that lead to oncogenesis have been extensively studied, little is known about the factors that cause the overexpression of PLK1 in CRC. DNA methylation was reported to be affecting the expression of PLK1 in some cancers. The study aims to investigate the contribution of genetic mutation and DNA methylation of the PLK1 gene to the overexpression of PLK1 in CRC. The study involves data mining from Catalogue of Somatic Mutations in Cancer (COSMIC) and Uni-ProtKB, Sanger sequencing on DNA from the cell lines HCT116, SW48, Co-lo320DM and T84 to analyse the possible mutation of PLK1. Other than that methylation status of the PLK1 promoter in CRC are also analysed by using mass spectrometry (MS) and pyrosequencing. Data from the COSMIC show the low incidences of PLK1 mutation for CRC (3.02%) with 46 mutations identified. One of the mutation p.R337Q (c.1010G > A) is located in the D-box which is an important motif for protein ubiquitination and eventually proteasomal degradation. Hence this mutation may potentially result in stabilisation of the PLK1 protein. Mutations are detected at the upstream silencer region, the promoter region and Exon1 in HCT116 but are not located at the protein binding or functioning site. Similarly, the same mutation at promoter region is detected in SW48. Differential trends of changes in methylation status of PLK1 in the IR treated CRC cell lines detected by MS reveal the possible association between the methylation and the radiosensitivity. Furthermore, pyrosequencing shows that PLK1 methylation status in tumour tissues with high expression of PLK1 is not significantly different from those with no How to cite this paper: Ng

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“…Many of these enriched genes are known/suspected to play a role in the regulation of HSC function ( S3 Table ). These include HoxB13 (a proposed tumor suppressor with described roles in cancer variety of tumor types) [ 28 – 30 ], CDKN1A (p21, a cyclin dependent kinase inhibitor that has been shown to be important in the long term maintenance of HSCs during stress, such as aging or serial transplant) [ 31 ], PLK4 (recently found to be deregulated in 70% of human lymphoma or myelodysplasia /leukemia clinical samples) [ 32 ] and Runx1t1 (known to play a role in human acute myeloid leukemia) [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Deficiency in Aryl Hydrocarbon Receptor (AHR) Expression throughout Aging Alters Gene Expression Profiles in Murine Long-Term Hematopoietic Stem Cells

et al. 2015

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Dysregulation of hematopoietic stem cell (HSC) signaling can contribute to the development of diseases of the blood system. Lack of aryl hydrocarbon receptor (AhR) has been associated with alterations in gene expression related to HSC function and the subsequent development of a myeloproliferative disorder in aging female mice. We sorted the most primitive population of HSCs with the highest stem cell potential (Long-term, or LT-HSCs) from 18-month-old AhR-null-allele (AhR-KO) and WT mice and analyzed gene expression using microarray to determine alterations in gene expression and cell signaling networks in HSCs that could potentially contribute to the aging phenotype of AhR-KO mice. Comparisons with previous array data from 8-week old mice indicated that aging alone is sufficient to alter gene expression. In addition, a significant number of gene expression differences were observed in aged LT-HSCs that are dependent on both aging and lack of AhR. Pathway analysis of these genes revealed networks related to hematopoietic stem cell activity or function. qPCR was used to confirm the differential expression of a subset of these genes, focusing on genes that may represent novel AhR targets due to the presence of a putative AhR binding site in their upstream regulatory region. We verified differential expression of PDGF-D, Smo, Wdfy1, Zbtb37 and Zfp382. Pathway analysis of this subset of genes revealed overlap between cellular functions of the novel AhR targets and AhR itself. Lentiviral-mediated knockdown of AhR in lineage-negative hematopoietic cells was sufficient to induce changes in all five of the candidate AhR targets identified. Taken together, these data suggest a role for AhR in HSC functional regulation, and identify novel HSC AhR target genes that may contribute to the phenotypes observed in AhR-KO mice.

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The deregulated promoter methylation of thePolo-like kinasesas a potential biomarker in hematological malignancies

Cited by 18 publications

References 49 publications

Investigating core genetic-and-epigenetic cell cycle networks for stemness and carcinogenic mechanisms, and cancer drug design using big database mining and genome-wide next-generation sequencing data

Investigating core genetic-and-epigenetic cell cycle networks for stemness and carcinogenic mechanisms, and cancer drug design using big database mining and genome-wide next-generation sequencing data

Exploration of Mutation and DNA Methylation of Polo-Like Kinase 1 (PLK1) in Colorectal Cancer

Deficiency in Aryl Hydrocarbon Receptor (AHR) Expression throughout Aging Alters Gene Expression Profiles in Murine Long-Term Hematopoietic Stem Cells

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