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Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review.

ABSTRACT: Loss-of-function events in tumor suppressor genes (TSGs) contribute to the development and progression of cutaneous malignant melanoma (CMM). Epigenetic alterations are the major mechanisms of TSG inactivation, in particular, silencing by promoter CpG-island hypermethylation. TSGs are valuable tools in diagnosis and prognosis and, possibly, in future targeted therapy. The aim of this narrative review is to outline bona fide TSGs affected by promoter CpG-island hypermethylation and their functional role in the progression of CMM. We conducted a systematic literature review to identify studies providing evidence of bona fide TSGs by cell line or animal experiments. We performed a broad first search and a gene-specific second search, supplemented by reference checking. We included studies describing bona fide TSGs in CMM with promoter CpG-island hypermethylation in which inactivating mechanisms were reported. We extracted data about protein role, pathway, experiments conducted to meet the bona fide criteria and hallmarks of cancer acquired by TSG inactivation. A total of 24 studies were included, describing 24 bona fide TSGs silenced by promoter CpG-island hypermethylation in CMM. Their effect on cell proliferation, apoptosis, growth, senescence, angiogenesis, migration, invasion or metastasis is also described. These data give further insight into the role of TSGs in the progression of CMM.

SUBMITTER: Guvenc C

PROVIDER: S-EPMC8508892 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review.

Güvenç Canan C Neckebroeck Fien F Antoranz Asier A Garmyn Marjan M van den Oord Joost J Bosisio Francesca Maria FM

International journal of molecular sciences 20211001 19

Loss-of-function events in tumor suppressor genes (TSGs) contribute to the development and progression of cutaneous malignant melanoma (CMM). Epigenetic alterations are the major mechanisms of TSG inactivation, in particular, silencing by promoter CpG-island hypermethylation. TSGs are valuable tools in diagnosis and prognosis and, possibly, in future targeted therapy. The aim of this narrative review is to outline bona fide TSGs affected by promoter CpG-island hypermethylation and their function ...[more]

PMID: 34639015

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Project description:BACKGROUND:Oral squamous cell carcinoma (OSCC) is a genetic and epigenetic disease. There is growing evidence to suggest that environmental factors due to epigenetic changes can be involved in the OSCC pathogenesis. Although tumor suppressor genes (TSGs) are commonly inactivated by promoter hypermethylation in human cancers, the epigenetic changes and the mechanism of TSGs in human OSCC remain unclear. We therefore assessed the methylation status of the TSGs, which are associated with epigenetic silencing in human cancers, OSCC cell lines, primary tumors, and normal oral mucosa. RESULTS:We used 14 TSGs that were originally identified in colon cancer to investigate the aberrant hypermethylation of these genes associated with transcriptional silencing in 10 OSCC cell lines. We found three TSGs, TFPI2, SOX17, and GATA4, that are robustly hypermethylated and are associated with transcriptional silencing in OSCC cell lines. The re-expression of the three genes was induced by 5-aza-2'-deoxycytidine (5-aza-dC) in cells in which these genes were not expressed or had a lack of expression. In 33 cases of primary OSCC tumors, promoter hypermethylation was detected for the TFPI2, SOX17, and GATA4 genes at (32/33) 97%, (22/33) 67%, and (11/33) 33%, respectively. Eleven normal oral mucosa samples showed no promoter hypermethylation for all three genes, which suggests that this promoter hypermethylation is cancer-specific. Bisulfite sequencing analysis confirmed the cancer-specific methylation of the TFPI2, SOX17, and GATA4 promoters in the OSCC cell lines and tumors but not in the normal oral mucosa samples. More importantly, the methylation status of TFPI2, GATA4, and SOX17 was significantly associated with OSCC patients' overall survival through TCGA DNA methylation database. CONCLUSIONS:We identified that TFPI2, SOX17, and GATA4 are frequently hypermethylated in human OSCC cells in a cancer-specific manner and that the transcriptional expression of these genes is regulated by promoter hypermethylation in OSCC. Our results highlight the great potential used as a synergistic biomarker set to improve the prognosis and therapeutic treatment for patients with OSCC.

Project description:UnlabelledMammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha-helical content, loosing the three alpha-helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C terminus of ovine PrP, since this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating and de novo infectious for naive homologous and wild-type PrP-expressing cells. Moreover, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies other than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha-helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions.ImportancePrions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion.

Project description:Objective: Pupil dilation patterns are outside of conscious control and provide information regarding neuropsychological processes related to deception, cognitive effort, and familiarity. This study examined the incremental utility of pupillometry on the Test of Memory Malingering (TOMM) in classifying individuals with verified traumatic brain injury (TBI), individuals simulating TBI, and healthy comparisons. Method: Participants were 177 adults across three groups: verified TBI (n = 53), feigned cognitive impairment due to TBI (SIM, n = 52), and heathy comparisons (HC, n = 72). Results: Logistic regression and ROC curve analyses identified several pupil indices that discriminated the groups. Pupillometry discriminated best for the comparison of greatest clinical interest, verified TBI versus simulators, adding information beyond traditional accuracy scores. Simulators showed evidence of greater cognitive load than both groups instructed to perform at their best ability (HC and TBI). Additionally, the typically robust phenomenon of dilating to familiar stimuli was relatively diminished among TBI simulators compared to TBI and HC. This finding may reflect competing, interfering effects of cognitive effort that are frequently observed in pupillary reactivity during deception. However, the familiarity effect appeared on nearly half the trials for SIM participants. Among those trials evidencing the familiarity response, selection of the unfamiliar stimulus (i.e., dilation-response inconsistency) was associated with a sizeable increase in likelihood of being a simulator. Conclusions: Taken together, these findings provide strong support for multimethod assessment: adding unique performance assessments such as biometrics to standard accuracy scores. Continued study of pupillometry will enhance the identification of simulators who are not detected by traditional performance validity test scoring metrics. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Dataset Information

Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review.

Publications

Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review.

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