DigitalUM :: Browsing by Subject "Methylation"

Browsing by Subject "Methylation"

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Open Access
Atypical meningioma: Histopathological, genetic, and epigenetic features to predict recurrence risk
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Marastoni, Elena; Barresi, Valeria
Grading assessed according to World Health Organization (WHO) criteria is a major prognostic factor for determining the risk of recurrence in patients with meningiomas and establishing the most appropriate therapeutic strategy after surgery. However, the main issue is to predict the recurrence risk of WHO grade 2 meningioma and, more specifically, of the atypical subtype. Indeed, owing to a reported recurrence rate of 50%, either radiotherapy or observation is currently considered an option after gross total surgical resection of atypical meningiomas. These heterogeneous clinical outcomes are likely related to the broad histopathological diagnostic criteria for this subtype, and whether meningiomas with only brain invasion should be classified as atypical remains controversial. Over the last few years, several studies have shown that DNA methylation profiling, next-generation sequencing, and transcriptomics can better stratify meningiomas for their recurrence risk than histology. The main limitations to the widespread use of these approaches to classify meningiomas are their high cost and the need for sophisticated technologies. However, all studies concurred that atypical meningiomas without chromosome 1p deletion display a low recurrence risk, suggesting that the assessment of this cytogenetic alteration could represent an easy and quick method to determine which patients could benefit from adjuvant treatment after surgery. In addition, prognostically unfavorable molecular groups can be distinguished using specific immunostainings, although further validation is required.
Open Access
Beyond p16 immunostaining: an overview of biomarkers in anal squamous intraepithelial lesions
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Albuquerque, Andreia; Rios, Elisabete; Medeiros, Rui
Histological grading of squamous intraepithelial lesions or intraepithelial neoplasia is fundamental for clinical management and for assessment of the risk of progression. Biomarkers are important for assisting correct grading of these lesions, reducing inter and intraobserver variability and most promising, for prognosis. Although p16 is the most studied biomarker in this setting, there are several other biomarkers that have been studied, reflecting also the need to find a better single or association option that can be more suitable, especially for classification purposes. A PubMed and Embase search was conducted from their inception until April 2018, aiming to identify biomarkers evaluated in histological samples of anal squamous intraepithelial lesions, other than p16. Information on “Ki-67”, “ProEx™ C”, “p53”, “human papillomavirus L1 capsid protein”, “stathmin-1”, “minichromosome maintenance protein”, “p21”, “proliferating cell nuclear antigen”, “histones”, “human papillomavirus E4”, “chromosomal abnormalities” and “methylation” was collected and reviewed. From these, the most studied biomarker was by far Ki-67. In many cases there were few studies performed for each biomarker, with no clear standardized interpretation of the immunostaining. An increased positive rate with more severe grades of lesions was shown in many cases. Prognostic data are limited and need to be further validated.
Open Access
Genetic and epigenetic alterations of tumor suppressor and tumor-related genes in gastric cancer
(Murcia : F. Hernández, 2002) Tamura, G.
Both genetic and epigenetic alterations of tumor suppressor and tumor-related genes involved in the pathogenesis of gastric cancer are reviewed here, and molecular pathways of gastric carcinogenesis are proposed. Gastric carcinomas are believed to evolve from native gastric mucosa or intestinal metaplastic mucosa that undergoes genetic and epigenetic alterations involving either the suppressor pathway (defects in tumor suppressor genes) or mutator pathway (defects in DNA mismatch repair genes). Methylation of E - c a d h e r i n in native gastric mucosa results in undifferentiated carcinomas (suppressor pathway), while methylation of hMLH1 results in differentiated foveolartype carcinomas (mutator pathway). The majority of d i fferentiated gastric carcinomas however, arise from intestinal metaplastic mucosa and exhibit structural alterations of tumor suppressor genes, especially p 5 3. They appear to be related to chronic injury, perhaps due to Helicobacter pylori infection. Approximately 20% of differentiated carcinomas (ordinary-type) have evidence of mutator pathway tumorigenesis. Mutations of E - c a d h e r i n are mainly involved in the progression of d i fferentiated carcinomas to undifferentiated tumors. The molecular pathways of gastric carcinogenesis depend on the histological background, and gastric carcinomas show distinct biological behaviors as a result of discernible cellular genetic and epigenetic alterations.
Open Access
Hyper-methylation of RIZ1 tumor suppressor gene is involved in the early tumorigenesis of hepatocellular carcinoma
(Murcia : F. Hernández, 2008) Piao, G-H.; Piao, W-H.; He, Y.; Zhang, H.; Wang, G-Q.; Piao, Z.
The retinoblastoma protein-interacting zinc finger gene RIZ1 is a putative tumor suppressor gene, and the inactivation of the RIZ1 is frequently found in tumors through a loss of mRNA expression. In order to understand the role of RIZ1 inactivation in the tumorigenesis of hepatocellular carcinoma (HCC), we detected the RIZ1 promoter methylation status in 39 HCCs using a methylation specific PCR (MSP) method, and carried out LOH study with marker P704. We also assessed the associations between the methylation status and clinicopathological parameters, tumor size, tumor differentiation, and fractional allelic loss (FAL). The results showed that the RIZ1 promoter methylated both in advanced tumors (>3 cm), (18/31, 58.0%) and in early tumors (<3 cm), (4/8, 50.0%). There were 54.6% (12/22) tumors with hyper-methylation in the low FAL group and 45.5% (10/22) in the high FAL group. Moreover, the DNA methylation of the RIZ1 promoter was found not only in the poorly differentiated tumors (12/22, 54.6%), but also in the well differentiated tumors (10/22, 45.5%). Among the 22 HCCs (22/39, 56.4%) that showed hypermethylation at the RIZ1 promoter region, 3 cases showed biallelic methylation. Interestingly, one case showed hyper-methylation on one allele and a loss of heterozygosity (LOH) on the other allele. In other words, 4 HCCs showed the biallelic inactivation of the RIZ1. These results suggest that the inactivation of the RIZ1 by DNA methylation at its promoter region is involved in the tumorigenesis of HCC, particularly in the early stage of disease.
Open Access
Methylation of histone H3 lysine 27 associated with apoptosis in osteosarcoma cells induced by staurosporine
(Murcia : F. Hernández, 2009) Cheng, Ming-Fang; Lee, Chian-Her; Hsia, Kan-Tai; Huang, , Guo-Shu; Lee, Herng-Sheng
The relationship between histone methylation and apoptosis, programmed cell death, is beginning to be explored. The objective of this study was to investigate the effects of staurosporine, a PKC inhibitor on the methylation of histone H3 in osteosarcoma cells. Following stimulation by staurosporine in vitro of G292 cells, a human osteosarcoma cell line with fibroblast-like phenotype, methylation of histone H3 was evaluated by western blotting and immunocytochemistry. G292 cells revealed the expression of cleaved PARP after incubation with staurosporine for 3 hours. Monomethyl lysine (K) 27 was induced by staurosporine at a concentration of 1, but no monomethyl K4 or K9 in histone H3 was seen. Dimethyl and trimethyl histone H3 K27 were also identified. There was no expression of dimethyl or trimethyl histone H3 K4 and K9. Expression of monomethyl histone H3 K27 was dose-dependent. The morphologic changes of apoptosis induced by staurosporine were observed under microscopy. Immunocytochemistry of monomethyl histone H3 K27 showed a weak signal in controls, a strong signal in staurosporine-treated tumor cells and a denser signal in the apoptotic cells. Our studies demonstrated that monomethyl histone H3 lysine 27 is expressed in staurosporine-induced apoptotic osteosarcoma cells. The findings may provide novel bridge information between the epigenetic episodes and apoptotic process
Open Access
PRMT1-dependent methylation of BRCA1 contributes to the epigenetic defense of breast cancer cells against ionizing radiation
(Springer Nature, 2020-08-06) González Guerrero, Rebeca; Piñero Madrona, Antonio; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; however, resistant cells rapidly initiate mechanisms to repair such damage. While DNA repair mechanisms responsible for cancer cell survival following DNA damage are understood, less is known about the epigenetic mechanisms resulting in resistance to radiotherapy. Although changes in DNA methylation are related to mechanisms of long-term resistance, it is more likely that the methylation state of a series of proteins could be responsible for the first-line of defense of cancer cells against irradiation. In this study, we observed that irradiation of breast cancer cells was accompanied by an overproduction in S-adenosylmethionine, which increases the activity of cellular methylases. We found that by activating PRMT1, irradiation triggers a BRCA1-dependent program that results in efficient DNA repair and inhibition of apoptosis. Depletion of PRMT1 in irradiated cells resulted in a switch of BRCA1 functions from repair and survival in the nucleus to activation of cell death signals in the cytoplasm. We conclude that by modulating the cellular localization of BRCA1, PRMT1 is an important regulator of the oncogenic functions of BRCA1, contributing to the epigenetic defense of breast cancer cells against ionizing radiation.
Open Access
Protein methylation, a new mechanism of p53 tumor suppressor regulation
(Murcia : F. Hernández, 2008) Scoumanne, A.; Chen, X.
The tumor suppressor p53 is the most frequently inactivated gene in human cancers. The p53 protein functions as a sequence-specific transcription factor to regulate key cellular processes, including cellcycle arrest, DNA repair, apoptosis, and senescence in response to stress signals. P53 is maintained at a low level in the cell, but becomes rapidly stabilized and activated in response to DNA damage, hypoxia, hyperproliferation, and other types of cellular stresses. The stability and transcriptional activity of p53 are tightly regulated through multiple post-translational modifications, such as phosphorylation, acetylation, and ubiquitination. Within the past few years, several studies have established that protein methylation is a novel mechanism by which p53 is regulated. Indeed, histone lysine methyltransferases KMT5 (Set9), KMT3C (Smyd2), and KMT5A (Set8) methylate p53 at specific C-terminal lysines. Lysine methylation enhances or suppresses p53 transcriptional activity depending on the methylation site. Furthermore, the lysine-specific demethylase KDM1 (LSD1) mediates p53 demethylation, which prevents p53 interaction with its co-activator 53BP1 to induce apoptosis. Finally, protein arginine methyltransferases CARM1 and PRMT1 are coactivators of p53 involved in the methylation of histones H3 and H4 to facilitate p53-mediated transcription. In response to cellular stresses, the interplay between p53 methylation, demethylation, and other post-translational modifications fine-tunes the activity of p53 to ultimately prevent tumor formation.
Open Access
Role of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Liu, Xiang; Ling, Zhi-Qiang
In recent years, frequent isocitrate dehydrogenase 1/2 (IDH1/IDH2) gene mutations were found in a variety of tumors, which specifically alter arginine residues of catalytic active site in IDH1/IDH2 and confer new enzymatic function of directly catalyzing alpha-ketoglutarate (α-KG) to R-2-hydroxyglutarate (2- HG). 2-HG could competitively inhibit α-KG–dependent enzymes and might therefore contribute to tumorigenesis. In addition, mutation status of IDH1/IDH2 is closely related to the progress and prognosis of certain tumors. Thus IDH1/IDH2 is considered to be a promising biomarker for early diagnosis and prognosis and targeted therapy. In this study, the current research on IDH1/IDH2 mutation, especially the mechanisms and clinical characteristics related to tumor, are reviewed.
Open Access
Silencing of SETD6 inhibits the tumorigenesis of oral squamous cell carcinoma by inhibiting methylation of PAK4 and RelA
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Huang, Wentao; Liu, Hongjing; Lv, Tianzhu
. Background. Oral squamous cell carcinoma (OSCC) is one of the most comment types of oral malignancies. SET-domain-containing protein 6 (SETD6) was recently identified as an important regulator of multiple signaling pathways through methylating protein substrates. Meanwhile, SETD6 is known to participate in multiple cancers. However, the role of SETD6 in OSCC remains unclear. Methods. Gene and protein expressions in OSCC cells or tissues were detected by RT-qPCR and western blot, respectively. In addition, CCK-8 assay was used to test the cell viability. A transwell assay was performed to measure cell migration and invasion. Flow cytometry was used to test cell apoptosis and cycle. Meanwhile, methylation-specific PCR (MSP) was used to detect the status of promoter methylation. Results. SETD6 was significantly upregulated in OSCC tissues. In addition, knockdown of SETD6 notably inhibited the proliferation and induced the apoptosis of OSCC cells. Furthermore, silencing of SETD6 notably suppressed the migration and invasion of OSCC cells. Meanwhile, SETD6 siRNA significantly inhibited the promoter methylation of RelA (NF-κB p65) and PAK4. Furthermore, SETD6 siRNA induced G1 arrest in OSCC cells. Conclusion. Knockdown of SETD6 inhibits the tumorigenesis of OSCC by suppressing promoter methylation of PAK4 and RelA. Therefore, our study might shed new light on exploring strategies for the treatment of OSCC.
Open Access
Targeting protein methylation in pancreatic cancer cells results in KRAS signaling imbalance and inhibition of autophagy
(Springer Nature, 2023-11-23) Martí Díaz, Román; Navarro, Ana; Tolivia, Jorge; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
Pancreatic cancer cells with mutant KRAS require strong basal autophagy for viability and growth. Here, we observed that some processes that allow the maintenance of basal autophagy in pancreatic cancer cells are controlled by protein methylation. Thus, by maintaining the methylation status of proteins such as PP2A and MRAS, these cells can sustain their autophagic activity. Protein methylation disruption by a hypomethylating treatment (HMT), which depletes cellular S-adenosylmethionine levels while inducing S-adenosylhomocysteine accumulation, resulted in autophagy inhibition and endoplasmic reticulum stress-induced apoptosis in pancreatic cancer cells. We observed that by reducing the membrane localization of MRAS, hypomethylation conditions produced an imbalance in KRAS signaling, resulting in the partial inactivation of ERK and hyperactivation of the PI3K/AKT–mTORC1 pathway. Interestingly, HMT impeded CRAF activation by disrupting the ternary SHOC2 complex (SHOC2/MRAS/PP1), which functions as a CRAF-S259 holophosphatase. The demethylation events that resulted in PP2A inactivation also favored autophagy inhibition by preventing ULK1 activation while restoring the cytoplasmic retention of the MiT/TFE transcription factors. Since autophagy provides pancreatic cancer cells with metabolic plasticity to cope with various metabolic stress conditions, while at the same time promoting their pathogenesis and resistance to KRAS pathway inhibitors, this hypomethylating treatment could represent a therapeutic opportunity for pancreatic adenocarcinomas.
Open Access
Targeting the epigenetic machinery of cancer cells
(Springer Nature, 2014-01-27) Fernández Pérez, María Piedad; Sáez Ayala, Magalí; Cabezas Herrera, Juan; Montenegro Arce, María Fernanda; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
Cancer is characterised by uncontrolled cell growth and the acquisition of metastatic properties. In most cases, the activation of oncogenes and/or deactivation of tumour suppressor genes lead to uncontrolled cell cycle progression and inactivation of apoptotic mechanisms. Although the underlying mechanisms of carcinogenesis remain unknown, increasing evidence links aberrant regulation of methylation to tumourigenesis. In addition to the methylation of DNA and histones, methylation of non-histone proteins, such as transcription factors, is also implicated in the biology and development of cancer. Because the metabolic cycling of methionine is a key pathway for many of these methylating reactions, strategies to target the epigenetic machinery of cancer cells could result in novel and efficient anti-cancer therapies. The application of these new epigenetic therapies could be of utility to promote E2F1-dependent apoptosis in cancer cells, avoid metastatic pathways and/or sensitise tumour cells to radiotherapy.
Open Access
The tumor suppressor RASSF1A in human carcinogenesis: an update
(Murcia : F. Hernández, 2005) Dammann, R.; Schagdarsurengin, U.; Seidel, C.; Strunnikova, M.; Rastetter, M.; Baier, K.; Pfeifer, G.P.
Loss of heterozygosity of the small arm of chromosome 3 is one of the most common alterations in human cancer. Most notably, a segment in 3p21.3 is frequently lost in lung cancer and several other carcinomas. We and others have identified a novel Ras effector at this segment, which was termed Ras Association Domain family 1 (RASSF1A) gene. RASSF1 consists of two main variants (RASSF1A and RASSF1C), which are transcribed from distinct CpG island promoters. Aberrant methylation of the RASSF1A promoter region is one of the most frequent epigenetic inactivation events detected in human cancer and leads to silencing of RASSF1A. Hypermethylation of RASSF1A was commonly observed in primary tumors including lung, breast, pancreas, kidney, liver, cervix, nasopharyngeal, prostate, thyroid and other cancers. Moreover, RASSF1A methylation was frequently detected in body fluids including blood, urine, nipple aspirates, sputum and bronchial alveolar lavages. Inactivation of RASSF1A was associated with an advanced tumor stage (e.g. bladder, brain, prostate, gastric tumors) and poor prognosis (e.g. lung, sarcoma and breast cancer). Detection of aberrant RASSF1A methylation may serve as a diagnostic and prognostic marker. The functional analyses of RASSF1A reveal an involvement in apoptotic signaling, microtubule stabilization and mitotic progression. The tumor suppressor RASSF1A may act as a negative Ras effector inhibiting cell growth and inducing cell death. Thus, RASSF1A may represent an epigenetically inactivated bona fide tumor suppressor in human carcinogenesis.

Browsing by Subject "Methylation"

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