scholarly journals Specific reversal of tumor-suppressor gene promoter hypermethylation with bovine oocyte extract

2013 ◽  
Vol 30 (1) ◽  
pp. 179-184 ◽  
Author(s):  
ZHENFEI WANG ◽  
HAIXIA GAO ◽  
HUIMIN WANG ◽  
XIAOLU REN ◽  
LURI BAO ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Bovine Oocyte

Tumor Suppressor Gene Promoter Hypermethylation in Serum of Breast Cancer Patients

2004 ◽  
Vol 10 (18) ◽  
pp. 6189-6193 ◽  
Author(s):  
Essel Dulaimi ◽  
Jeanne Hillinck ◽  
Inmaculada Ibanez de Caceres ◽  
Tahseen Al-Saleem ◽  
Paul Cairns
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Patients ◽  
Tumor Suppressor Gene ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Breast Cancer Patients

scholarly journals Tumor-suppressor Gene Promoter Hypermethylation in Saliva of Head and Neck Cancer Patients

2012 ◽  
Vol 5 (5) ◽  
pp. 321-326 ◽  
Author(s):  
Dmitry A. Ovchinnikov ◽  
Matthew A. Cooper ◽  
Pratibala Pandit ◽  
William B. Coman ◽  
Justin J. Cooper-White ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Tumor Suppressor ◽  
Head And Neck ◽  
Cancer Patients ◽  
Tumor Suppressor Gene ◽  
Neck Cancer ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Suppressor Gene

The Tumor Suppressor Role of the Ras Association Domain Family 10

2020 ◽  
Vol 20 (18) ◽  
pp. 2207-2215
Author(s):  
Yulong Hou ◽  
Shuofeng Li ◽  
Wei Du ◽  
Hailong Li ◽  
Rumin Wen
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Gene Promoter ◽  
Disease Free Survival ◽  
Suppressor Gene ◽  
Detection Methods ◽  
Tumor Type ◽  
Domain Family ◽  
Invasion And Migration ◽  
Cancer Breast

The Ras association domain family 10(RASSF10), a tumor suppressor gene, is located on human chromosome 11p15.2, which is one of the members homologous to other N-terminal RASSF families obtained through structural prediction. RASSF10 plays an important role in inhibiting proliferation, invasion, and migration, inducing apoptosis, making cancer cells sensitive to docetaxel, and capturing G2/M phase. Some studies have found that RASSF10 may inhibit the occurrence and development of tumors by regulating Wnt/β-catenin, P53, and MMP2. Methylation of tumor suppressor gene promoter is a key factor in the development and progression of many tumors. Various methylation detection methods confirmed that the methylation and downregulation of RASSF10 often occur in various tumors, such as gastric cancer, lung cancer, colon cancer, breast cancer, and leukemia. The status of RASSF10 methylation is positively correlated with tumor size, tumor type, and TNM stage. RASSF10 methylation can be used as a prognostic factor for overall survival and disease-free survival, and is also a sign of tumor diagnosis and sensitivity to docetaxel chemotherapy. In this review, we mainly elucidate the acknowledged structure and progress in the verified functions of RASSF10 and the probably relevant signaling pathways.

scholarly journals Epigenetic Regulation of the Human Retinoblastoma Tumor Suppressor Gene Promoter by CTCF

2007 ◽  
Vol 67 (6) ◽  
pp. 2577-2585 ◽  
Author(s):  
Inti A. De La Rosa-Velázquez ◽  
Héctor Rincón-Arano ◽  
Luis Benítez-Bribiesca ◽  
Félix Recillas-Targa
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Epigenetic Regulation ◽  
Gene Promoter ◽  
Suppressor Gene ◽  
Retinoblastoma Tumor Suppressor ◽  
Human Retinoblastoma ◽  
Retinoblastoma Tumor

scholarly journals Mutations in NOTCH1 PEST Domain Orchestrate CCL19-Driven Homing of Chronic Lymphocytic Leukemia (CLL) Cells By Modulating the Tumor Suppressor Gene DUSP22

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 969-969
Author(s):  
Francesca Arruga ◽  
Branimir Gizdic ◽  
Cinzia Bologna ◽  
Simona Cignetto ◽  
Roberta Buonincontri ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Dna Methyltransferase ◽  
Gene Promoter ◽  
Suppressor Gene ◽  
Lymphocytic Leukemia ◽  
Ccr7 Expression ◽  
Stat3 Phosphorylation ◽  
Gene And Protein Expression ◽  
The Impact

Abstract BACKGROUND . NOTCH1 PEST domain mutations were among the first to be identified using whole exome sequencing and their prevalence and prognostic power for CLL patients has since been extensively studied. Nevertheless, the functional contribution of NOTCH1 and the impact of its mutations in CLL remain poorly understood. This is mainly due to the intrinsic limits in using primary CLL cells and to the rapid inactivation of the NOTCH1 pathway in vitro. AIM. The aim of the study was to highlight the NOTCH1-dependent mechanisms contributing to CLL pathogenesis and progression and the effects of PEST mutations in this disease context. RESULTS. By using the CRISPR/Cas9 technology, we first generated a cellular model either lacking NOTCH1 (Mec-1/KO) or expressing it in its wild-type or mutated forms. RNA-seq analysis of the transcriptome of Mec-1/WT and /KO cells, highlighted signaling and migration as the most prominently down-regulated pathways in KO cells. These findings were confirmed by showing that Mec-1/KO cells migrated significantly less towards CCL19 than their WT counterparts, as the result of the down-modulation of CCR7, the CCL19 receptor. Mechanistically, Mec-1/KO were characterized by increased expression of the tumor suppressor gene DUSP22, a phosphatase that negatively regulates MAPK and STAT3 signaling, in turn responsible for CCR7 gene transcription. Up-regulation of DUSP22 in Mec-1/KO was caused by decreased methylation of the gene promoter, as shown using a methylation specific PCR. Re-expression of the NOTCH1 Intracellular Domain (NICD) rescued the phenotype, increasing methylation of the DUSP22 promoter, which in turn led to decreased gene and protein expression. Mec-1 cells with reconstituted NICD expression showed increased STAT3 phosphorylation, CCR7 expression and, ultimately, migrated more actively in response to CCL19. Importantly, reconstitution with an NICD carrying the PEST domain mutation most commonly found in patients (ΔCT_7541-7542), significantly enhanced all these events, including DUSP22methylation, STAT3 phosphorylation, CCR7 expression, generating cells with the highest chemotactic responses to CCL19. NOTCH1 directly participates to the epigenetic regulation of DUSP22, by conditioning the activity of the DNA methyltransferase 3A (DNMT3A) on the gene promoter. By binding RBPJk, the NICD displaces HDAC1 from the repressor complex and initiates NOTCH1-dependent signaling. Consequently, free HDAC1 binds to and stabilizes DNMT3A, promoting its activity on DUSP22promoter. These results were first corroborated in a large cohort of CLL (n=113) carrying mutations in NOTCH1 PEST domain (ΔCT_7541-7542)at the clonal (>12%) or subclonal (≤12%) level. The clonally mutated subset showed significant downregulation of DUSP22expression and gene promoter hypermethylation compared to subclonal samples. Consistently, the clonal subset displayed higher constitutive STAT3 phosphorylation, expressed higher levels of CCR7 and migrated more efficiently to CCL19 than subclonally mutated CLL. The second confirmation was obtained by studying a Mec-1 variant with PEST domain mutation (Mec-1/PEST), generated using the CRISPR/Cas9 system. Like primary cells, Mec-1/PEST needed the ligand to initiate signaling. As predicted, the mutant NICD was more stable and more transcriptionally active. Consistently, these cells had the lowest DUSP22 levels and the highest CCR7 expression. When Mec-1/PEST were xenografted in immunocompromised mice, activation of the NOTCH1 pathway was more pronounced than that of Mec-1/WT cells. In keeping with their minimal expression of DUSP22, Mec-1/PEST cells were characterized by markedly increased metastatic properties, with extensive colonization of the liver, the spleen, and the brain, at variance with the other cell variants. CONCLUSIONS . Considered together, these results show that PEST mutations increase NICD stability, in turn affecting a complex nuclear balance. The final outcome for the CLL cell is decreased expression of the tumor suppressor gene DUSP22 and increased chemotaxis towards CCL19. As this chemokine regulates homing to secondary organs, conceivably NOTCH1 mutations might favor CLL recirculation to lymph node and spleen, where the local environment triggers proliferation and protects from apoptosis, two conditions that are associated with a more aggressive disease and an unfavorable prognosis. Disclosures Coscia: Karyopharm: Research Funding; Janssen: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria; ROCHE: Honoraria, Other: Advisory board. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria.

Identification of ID4 as a Cooperating Second Hit for T Cell Lymphoma Development in PU.1 UREΔ/Δ Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2613-2613
Author(s):  
Bronwyn M. Owens ◽  
Li Yu ◽  
Ulrich Steidl ◽  
Jeffrey L. Kutok ◽  
Linda K. Clayton ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Regulatory Element ◽  
Tumor Development ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Promoter Regions ◽  
Hematopoietic Stem

Abstract The transcription factor PU.1 is a key regulator of hematopoiesis and is essential for normal hematopoietic stem cell (HSC) function and myeloid and lymphoid differentiation. Knockout mice are embryonic or neonatal lethal and exhibit an early differentiation block at the transition from HSC to CMP and CLP. Mice with a deletion of a critical upstream regulatory element (URE) at −14kb has been deleted exhibited decreased PU.1 expression in HSC, progenitors and B cells to 20% of normal levels. In contrast, an increase of PU.1 expression was detected in early thymic progenitors. UREΔ/Δ animals exhibited a block in normal thymocyte differentiation and frequently progressed to fatal T cell lymphomas between 3 and 8 months of age. Tumors were clonal and transplantable into NOD-SCID recipients. Since aberrant PU.1 expression constituted the initiating mutation, we sought to identify cooperating mutations contributing to tumor development by surveying the genome for hypermethylated promoter regions using restriction landmark global scanning. Methylation patterns revealed a characteristic epigenetic footprint leading to selective tumor suppressor gene silencing in transformation of lymphoid but not myeloid UREΔ/Δ progenitors, since DNA methylation was significantly lower in the AML samples compared with lymphomas. One of the corresponding methylated genes that was silenced in all lymphomas analyzed but none of the AMLs was identified as Idb4 (encoding ID4, inhibitor of DNA binding 4). This observation is consistent with data describing ID4 as a strong tumor suppressor gene which is frequently silenced in neoplasms. The expression of Idb4 in 6 additional lymphomas was assessed by quantitative RT-PCR and showed a strong correlation between promoter hypermethylation and Idb4 downregulation. To test whether Idb4 silencing through promoter hypermethylation can be pharmacologically reversed, a UREΔ/Δ lymphoma cell line was established and treated with 5-aza-2′deoxycytidine. We found that Idb4 expression was restored to normal levels following increasing concentrations of this demethylating agent. Finally, we analyzed the functional relevance of the Idb4 downregulation by restoring Idb4 expression in the UREΔ/Δ tumor line. UREΔ/Δ lymphoma cells reexpressing Idb4 had a marked reduction in both the in vitro growth rate and the ability to cause tumors after transplantation into NOD/SCID recipient mice, indicating that Idb4 is a potent suppressor of UREΔ/Δ thymic tumorigenicity. Taken together, we provide evidence that epigenetic DNA modifications contribute significantly and selectively to lymphoid transformation in UREΔ/Δ mice, and suggest a role for Idb4 repression as a second event in PU.1-initiated transformation of lymphoid precursors.

Comprehensive Analysis of p16INK4a in Childhood Acute Lymphoblastic Leukemia Reveals Homozygous Deletion, Haploinsufficiency and Acquired Isodisomy at the 9p Locus with Intact p16INK4a.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4332-4332
Author(s):  
Sarina Sulong ◽  
Julie Irving ◽  
Marian Case ◽  
Lynne Minto ◽  
Nick Bown ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Somatic Mutation ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Comprehensive Analysis ◽  
Childhood All

Abstract Genetic alterations including chromosomal translocation, promoter hypermethylation, somatic mutation and gene deletion are believed to play a key role in the leukemogenic process in childhood acute lymphoblastic leukemia (ALL). The p16INK4a (CDKN2A/MTS1/p16/INK4a) gene located on chromosome 9p21 is a tumor suppressor gene whose product can block cell division during the G1/S phase of the cell cycle. Inactivation of p16INK4a in ALL can occur by deletion, promoter hypermethylation or somatic mutation. However, published reports are inconsistent in terms of both incidence and route of p16INK4a inactivation suggesting that a detailed analysis of all possible modes of inactivation in a large cohort is essential to clarify the status of this gene in leukemogenesis. In this study, we report the findings of a comprehensive analysis of p16INK4a in 115 DNA samples with childhood ALL (86 cases at presentation and 29 cases at relapse) in which a combination of techniques including, fluorescence in situ hybridization (FISH), mapping arrays, denaturing high performance liquid chromatography (dHPLC) and methylation specific-PCR (MSP) were used to assess the mode of inactivation of this gene. Data from a genome-wide screening in 86 presentation cases and 20 of 29 relapse cases using Affymetrix Mapping 10K and/or 50K single nucleotide polymorphism (SNP) microarray technique showed loss of heterozygosity (LOH) at the p16INK4a locus in 21% (22/106) of cases (14 at presentation and 8 at relapse), 14 (8 at presentation and 6 at relapse) with an associated loss of copy number and 8 (6 at presentation and 2 at relapse) with a normal copy number, indicative of acquired isodisomy (AID). FISH analysis on 19 of the 22 confirmed that those cases with LOH and copy number loss had either p16INK4a homozygous (n=6) or hemizygous (n=6) deletion and those with LOH associated with AID (n=7) retained 2 copies. Mutation and methylation analyses were performed on those cases identified to have one p16INK4a allele or retention of both alleles. Partial methylation of p16INK4a was found in only 1 case. Mutational screening by dHPLC of the coding region revealed a somatic mutation, H83Y, in a subpopulation of leukemic blasts in one patient at relapse. Three common SNPs were identified including A148T in exon 2 and 500C>G and 540 C>T in the 3′ UTR. These data show that mutation and hypermethylation of p16INK4a are rare events in childhood ALL but that homozygous and hemizygous deletion is relatively common. The loss of only one p16INK4a allele in this latter group, without evidence for mutation or hypermethylation of the remaining one suggests that p16INK4a may be haploinsufficient in ALL. The finding that LOH on 9p locus is common but in nearly 40% of these cases is associated with AID with intact p16INK4a, suggests the existence of another tumor suppressor gene or oncogene in this region, which may have importance in leukemogenesis.

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