scholarly journals PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Jorge A. Benitez ◽  
Jianhui Ma ◽  
Matteo D’Antonio ◽  
Antonia Boyer ◽  
Maria Fernanda Camargo ◽  
...  
Keyword(s):  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Growth Defect ◽  
Tumour Suppressor Genes ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion ◽  
Therapeutic Opportunity ◽  
Associated Function

Abstract Glioblastoma (GBM) is the most lethal type of human brain cancer, where deletions and mutations in the tumour suppressor gene PTEN (phosphatase and tensin homolog) are frequent events and are associated with therapeutic resistance. Herein, we report a novel chromatin-associated function of PTEN in complex with the histone chaperone DAXX and the histone variant H3.3. We show that PTEN interacts with DAXX and, in turn PTEN directly regulates oncogene expression by modulating DAXX-H3.3 association on the chromatin, independently of PTEN enzymatic activity. Furthermore, DAXX inhibition specifically suppresses tumour growth and improves the survival of orthotopically engrafted mice implanted with human PTEN-deficient glioma samples, associated with global H3.3 genomic distribution changes leading to upregulation of tumour suppressor genes and downregulation of oncogenes. Moreover, DAXX expression anti-correlates with PTEN expression in GBM patient samples. Since loss of chromosome 10 and PTEN are common events in cancer, this synthetic growth defect mediated by DAXX suppression represents a therapeutic opportunity to inhibit tumorigenesis specifically in the context of PTEN deletion.

Use of Monozygotic Twins in Search for Breast Cancer Susceptibility Loci

Twin Research ◽  
2001 ◽  
Vol 4 (4) ◽  
pp. 251-259 ◽  
Author(s):  
Asta Försti ◽  
Qianren Jin ◽  
Lena Sundqvist ◽  
Magnus Söderberg ◽  
Kari Hemminki
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Monozygotic Twins ◽  
Monozygotic Twin ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes ◽  
Twin Model

AbstractWe have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel, including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.

Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification

2017 ◽  
Vol 71 (4) ◽  
pp. 351-359 ◽  
Author(s):  
Marc L Ooft ◽  
Jolique van Ipenburg ◽  
Rob van Loo ◽  
Rick de Jong ◽  
Cathy Moelans ◽  
...  
Keyword(s):  
Treatment Options ◽  
Disease Free Survival ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Molecular Profile ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes ◽  
Dependent Probe

AimsTo assess differences in methylation profiles, and thus pathogenesis, between Epstein-Barr virus (EBV)-positive and negative nasopharyngeal carcinomas (NPCs). Also, promoter hypermethylation is a common phenomenon in early carcinogenesis to inactivate tumour suppressor genes. Since epigenetic changes are reversible, the therapeutic application of methylation inhibitors could provide treatment options.MethodsWe evaluated promoter hypermethylation profiles of 22 common tumour suppressor genes in 108 NPCs using methylation-specific multiplex ligation-dependent probe amplification. Correlation between methylation, clinicopathological features (including EBV) and survival was examined. Cluster analysis was also performed.ResultsHypermethylation of RASSF1A and ESR1 was significantly more frequent in EBV-positive NPC, while hypermethylation of DAPK1 was more frequent in EBV-negative NPC. In logistic regression, age, with EBV-positive NPC occurring at earlier age, and RASSF1, with RASSF1 hypermethylation being more frequent in EBV-positive NPC, remained significant. In EBV-positive NPC, hypermethylation of RASSF1A predicted worse overall survival (OS) (HR 3.058,95% CI 1.027 to 9.107). In EBV-negative NPC, hypermethylated adenomatous polyposis coli (APC) was a predictor of poor disease-free survival (DFS) (HR 6.868, 95% CI 2.142 to 22.022).ConclusionThere are important epigenetic differences between EBV-negative and EBV-positive NPCs, with EBV-negative NPC having a more similar hypermethylation profile to other head and neck squamous cell carcinomas than EBV-positive NPC. Hypermethylation of RASSF1A might contribute to worse OS in EBV-positive NPC, and may be an important event in the pathogenesis of EBV-infected NPC. Hypermethylation of APC might contribute to worse DFS in EBV-negative NPC.

scholarly journals Non-accidental structural chromosome aberrations in established monkey B-lymphocyte cell lines

Biologija ◽  
2020 ◽  
Vol 65 (4) ◽  
Author(s):  
Daredzhan Araviashvili ◽  
Olga Chzhu ◽  
Igor Marinich ◽  
Irina Danilova
Keyword(s):  
Cell Lines ◽  
Chromosomal Aberrations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Chromosome 8 ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes ◽  
Cultivation In Vitro ◽  
Lymphocyte Cell

Established primate lymphocyte cell lines obtained from tumour samples and from EBV-positive monkeys served us as the model system for studying the role of genetic factors and chromosomal abnormalities in malignization. The investigation of chromosome regions and genes involved in chromosomal aberrations leading to malignization in these lines was the aim of our work. Cytogenetic analysis was performed at different stages of cultivation in vitro. To determine the oncogenes and tumour suppressor genes located on aberrant chromosomes, data on mapping rhesus macaque genes, and high similarity of human and monkey karyotypes were used. We found that, in the line obtained from lymphomatous baboon tissue, the inactivation of tumour suppressor gene RB1 on chromosome 17 after chromosomal rearrangement is one of the most probable causes of in vivo malignization. Chromosomal aberrations at the region of oncogene c-Ki-ras and tumour suppressor gene TP53 change the proliferative status and differentiation in established cell lines obtained from healthy but EBV-seropositive primates. The other cause of malignization in these lines is an increase in expression of the oncogene c-myc caused by trisomy of chromosome 8 where c-myc is located. Structural aberrations in established primate cell lines affecting several chromosomal loci were identified as: (1) causing the proto-oncogene activation – the central event in the tumour clone occurrence, and (2) deactivating tumour suppressor genes. The change in the chromosome number leads to increase in oncogenic products and to damage of regulatory functions associated with cell proliferation.

scholarly journals CTCF Expression Is Essential for Somatic Cell Viability and Protection against Cancer

2018 ◽  
Author(s):  
Charles G. Bailey ◽  
Cynthia Metierre ◽  
Julie Feng ◽  
Kinsha Baidya ◽  
Galina N. Filippova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Somatic Cells ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Absolute Requirement ◽  
The Impact

CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in CTCF, which we have shown, functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. We examined the consequences of CTCF depletion in immortalised human and mouse cells using shRNA knockdown and CRISPR/Cas9 genome editing and examined the growth and development of heterozygous Ctcf (Ctcf+/-) mice. We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF-altered endometrial carcinoma. Knockdown and CRISPR/Cas9-mediated editing of CTCF reduced the cellular growth and colony-forming ability of K562 cells. CTCF knockdown also induced cell cycle arrest and a pro-survival response to apoptotic insult. However, in p53 shRNA-immortalised Ctcf+/- MEFs we observed the opposite: increased cellular proliferation, colony formation, cell cycle progression and decreased survival after apoptotic insult compared to wild type MEFs. CRISPR/Cas9-mediated targeting in Ctcf+/- MEFs revealed a predominance of in-frame microdeletions in Ctcf in surviving clones, however protein expression could not be ablated. Examination of CTCF mutations in endometrial cancers showed locus-specific alterations in gene expression due to CTCF haploinsufficiency, in concert with downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes. Depletion of CTCF expression imparts a dramatic negative effect on normal cell function. However, CTCF haploinsufficiency can have growth-promoting effects consistent with known cancer hallmarks in the presence of additional genetic hits. Our results confirm the absolute requirement for CTCF expression in somatic cells and provide definitive evidence of CTCF’s role as a haploinsufficient tumour suppressor gene. CTCF genetic alterations in endometrial cancer indicate that gene dysregulation is a likely consequence of CTCF loss, contributing to, but not solely driving cancer growth.

scholarly journals Intestinal epithelial-specific PTEN inactivation results in tumor formation

2011 ◽  
Vol 301 (5) ◽  
pp. G856-G864 ◽  
Author(s):  
Do-Sun Byun ◽  
Naseem Ahmed ◽  
Shannon Nasser ◽  
Joongho Shin ◽  
Sheren Al-Obaidi ◽  
...  
Keyword(s):  
Cell Fate ◽  
Intestinal Epithelium ◽  
Suppressor Gene ◽  
Major Effect ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of phosphatidylinositol 3-kinase (PI3K) signaling that is frequently inactivated in colorectal cancer through mutation, loss of heterozygosity, or epigenetic mechanisms. The aim of this study was to determine the effect of intestinal-specific PTEN inactivation on intestinal epithelial homeostasis and tumorigenesis. PTEN was deleted specifically in the intestinal epithelium, by crossing PTEN Lox/ Lox mice with villin Cre mice. PTEN was robustly expressed in the intestinal epithelium and maximally in the differentiated cell compartment. Targeted inactivation of PTEN in the intestinal epithelium of PTEN Lox/ Lox/villin Cre mice was confirmed by genotyping, immunohistochemistry, and qPCR. While intestinal-specific PTEN deletion did not have a major effect on cell fate determination or proliferation in the small intestine, it did increase phosphorylated (p) protein kinase B (AKT) expression in the intestinal epithelium, and 19% of animals developed small intestinal adenomas and adenocarcinomas at 12 mo of age. These tumors demonstrated pAKT and nuclear β-catenin staining, indicating simultaneous activation of the PI3K/AKT and Wnt signaling pathways. These findings demonstrate that, while PTEN inactivation alone has a minimal effect on intestinal homeostasis, it can facilitate tumor promotion upon deregulation of β-catenin/TCF signaling, further establishing PTEN as a bona fide tumor suppressor gene in intestinal cancer.

scholarly journals CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer

2018 ◽  
Vol 19 (12) ◽  
pp. 3832 ◽  
Author(s):  
Charles Bailey ◽  
Cynthia Metierre ◽  
Yue Feng ◽  
Kinsha Baidya ◽  
Galina Filippova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Somatic Cells ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Absolute Requirement ◽  
The Impact

CCCTC-binding factor (CTCF) is a conserved transcription factor that performs diverse roles in transcriptional regulation and chromatin architecture. Cancer genome sequencing reveals diverse acquired mutations in CTCF, which we have shown functions as a tumour suppressor gene. While CTCF is essential for embryonic development, little is known of its absolute requirement in somatic cells and the consequences of CTCF haploinsufficiency. We examined the consequences of CTCF depletion in immortalised human and mouse cells using shRNA knockdown and CRISPR/Cas9 genome editing as well as examined the growth and development of heterozygous Ctcf (Ctcf+/−) mice. We also analysed the impact of CTCF haploinsufficiency by examining gene expression changes in CTCF-altered endometrial carcinoma. Knockdown and CRISPR/Cas9-mediated editing of CTCF reduced the cellular growth and colony-forming ability of K562 cells. CTCF knockdown also induced cell cycle arrest and a pro-survival response to apoptotic insult. However, in p53 shRNA-immortalised Ctcf+/− MEFs we observed the opposite: increased cellular proliferation, colony formation, cell cycle progression, and decreased survival after apoptotic insult compared to wild-type MEFs. CRISPR/Cas9-mediated targeting in Ctcf+/− MEFs revealed a predominance of in-frame microdeletions in Ctcf in surviving clones, however protein expression could not be ablated. Examination of CTCF mutations in endometrial cancers showed locus-specific alterations in gene expression due to CTCF haploinsufficiency, in concert with downregulation of tumour suppressor genes and upregulation of estrogen-responsive genes. Depletion of CTCF expression imparts a dramatic negative effect on normal cell function. However, CTCF haploinsufficiency can have growth-promoting effects consistent with known cancer hallmarks in the presence of additional genetic hits. Our results confirm the absolute requirement for CTCF expression in somatic cells and provide definitive evidence of CTCF’s role as a haploinsufficient tumour suppressor gene. CTCF genetic alterations in endometrial cancer indicate that gene dysregulation is a likely consequence of CTCF loss, contributing to, but not solely driving cancer growth.

scholarly journals Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

2015 ◽  
Vol 370 (1673) ◽  
pp. 20140222 ◽  
Author(s):  
Aleah F. Caulin ◽  
Trevor A. Graham ◽  
Li-San Wang ◽  
Carlo C. Maley
Keyword(s):  
Cancer Risk ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Size Analysis ◽  
Tumour Suppressor Genes ◽  
Division Rate ◽  
Somatic Evolution ◽  
Mammalian Genomes

Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.

Human Papillomaviruses, Tumour Suppressor Genes and Cervical Cancer

1993 ◽  
Vol 4 (3) ◽  
pp. 128-134 ◽  
Author(s):  
G J Inman ◽  
I D Cook ◽  
R K W Lau
Keyword(s):  
Current Knowledge ◽  
Squamous Carcinoma ◽  
Molecular Study ◽  
Suppressor Gene ◽  
Hpv Infection ◽  
Tumour Suppressor Gene ◽  
Human Papillomaviruses ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
E6 And E7

There is now a considerable body of evidence that links HPV infection with anogenital squamous carcinoma, particularly for specific ‘high risk’ HPV types (HPV16 and 18) and invasive carcinoma of the cervix. Recent advances in the molecular study of these viruses have elucidated some potential mechanisms by which they may contribute to the development of these diseases. In this review we concentrate on the interactions of 2 of the HPV encoded proteins, E6 and E7, with cellular tumour suppressor gene products. We provide a model of how these interactions may be important in tumourigenesis and draw together current knowledge of this exciting and rapidly evolving field.

The molecular biology of Wilms' tumour

2001 ◽  
Vol 3 (13) ◽  
pp. 1-16 ◽  
Author(s):  
Keith W. Brown ◽  
Karim T.A. Malik
Keyword(s):  
Kidney Development ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Kidney Neoplasm ◽  
Tumour Suppressor Genes ◽  
Loss Of Function ◽  
Wilms Tumour ◽  
Suppressor Genes ◽  
Renal Stem Cells

Wilms' tumour (WT; nephroblastoma), a kidney neoplasm, is one of the most frequently occurring solid tumours of childhood. It arises from the developing kidney by genetic and epigenetic changes that lead to the abnormal proliferation of renal stem cells (metanephric blastema). WT serves as a paradigm for understanding the relationship between loss of developmental control and gain of tumourigenic potential. In particular, loss of function of tumour suppressor genes has been implicated in the development of WT, and the Wilms' tumour suppressor gene WT1 (at chromosome 11p13) was the second tumour suppressor gene to be cloned, after the retinoblastoma gene RB-1. WT1 plays an essential role in kidney development, but is mutated in only approximately 20% of WTs, which suggests that further lesions and genetic loci are involved in Wilms' tumourigenesis. Other chromosomal regions associated with WT include 7p, 11p15, 16q and 17q. Although many of these loci probably contain tumour suppressor genes, imprinted genes (genes showing expression of only one parental allele) and oncogenes have also been implicated in WT. Some loci have been shown to be associated with particular clinical outcomes, suggesting that they might be used to determine prognosis, and especially to identify poor prognostic subgroups that can be targeted for aggressive and/or novel therapies.

scholarly journals Pituitary tumours

Reproduction ◽  
2001 ◽  
pp. 363-371 ◽  
Author(s):  
◽  
WE Farrell ◽  
RN Clayton
Keyword(s):  
Cell Types ◽  
Pituitary Tumour ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Loss Of Function ◽  
Pituitary Tumours ◽  
Traditional Approaches ◽  
Different Cell Types

Pituitary tumours are a common type of intracranial neoplasm and, depending on the cell type of origin, have diverse endocrine and reproductive effects. The developmental biology of the different cell types is understood to result from a sequential activation of a cascade of transcription factors, and mutations in these factors result in various forms of hypopituitarism. Tumours in the pituitary gland arise from activation of dominantly acting oncogenes such as gsp, or from loss of function of a series of tumour suppressor genes such as MEN1. Abnormal patterns of DNA methylation may be implicated in the allelic losses that cause tumour suppressor gene silencing. The different clinically recognized types of pituitary tumour are currently treated by medical therapies such as dopamine and somatostatin agonists, surgery or radiotherapy. However, these treatments are not entirely satisfactory and recent advances in gene therapy may offer valuable new therapeutic opportunities for patients with aggressive tumours that fail to respond to traditional approaches.

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