Epigenetic reprogramming as a key contributor to melanocyte malignant transformation

Molognoni, Fernanda; Cruz, Adriana Taveira da; Meliso, Fabiana Marcelino; Morais, Alice Santana; Souza, Cláudia; Xander, Patrícia; Bischof, Jared M.; Costa, Fabrício F.; Soares, Marcelo B.; Liang, Gangning; Jones, Peter A.; Jasiulionis, Miriam Galvonas

doi:10.4161/epi.6.4.14917

Cited by 41 publications

(59 citation statements)

References 57 publications

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“…H3K27me3 and H3K9me3 were increased [21]. These findings are consistent with data from melanoma cell lines showing global hypo-methylation compared to melanocytes [22][23][24] with 11 out of 14 types of repetitive DNA elements being hypo-methylated [22].…”

Section: Dna Methylation In Melanoma Developmentsupporting

confidence: 91%

“…One model used to investigate epigenetic alterations during melanoma development utilizes sequential cycles of anchorage blockade to transform mouse melanocytes resulting in cell lines that show different degrees of aggressiveness and in vivo tumor growth potential, to mimic different stages of melanomagenesis [21]. Investigating DNA and histone modifications in this model showed substantial epigenetic changes as global DNA methylation was decreased while multiple histone modifications including H4K16ac, H3K4me3,…”

Section: Dna Methylation In Melanoma Developmentmentioning

confidence: 99%

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Epigenetics in Melanoma Development and Drug Resistance

Hammerlindl¹,

Schaider²

2018

Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

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Melanomas, which originate from melanocytic cells, mainly develop in the skin but can also arise at other body sites. The disease accounts for approximately 90% of deaths related to cutaneous tumors with late stage metastatic melanoma having a very poor prognosis of 6-9 month median survival for untreated patients. Research in the last decades resulted in ground-breaking discoveries of melanoma genetics and biology. High frequency mutations in genes like BRAF, NRAS and KIT, which lead to hyper-activation of the MAPK signaling pathway, drive melanoma progression. Targeting the MAPK signaling pathway has successfully been translated into effective therapies that significantly improve patient survival. Despite the unquestionable importance of such genetic events, the involvement of epigenetic alterations for melanoma development, and resistance to aforementioned therapies is becoming increasingly apparent. In this chapter, epigenetic alterations commonly found in melanoma are introduced, with a focus on histone and DNA modifications and their relevance for melanoma development, progression and therapy response. Detailed knowledge about this emerging aspect of melanoma research will help to understand the plastic nature of melanoma and set the foundation for novel treatment strategies that target aberrant gene regulation on genetic and epigenetic levels.

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Section: Dna Methylation In Melanoma Developmentsupporting

confidence: 91%

Section: Dna Methylation In Melanoma Developmentmentioning

confidence: 99%

Epigenetics in Melanoma Development and Drug Resistance

Hammerlindl¹,

Schaider²

2018

Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

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“…These findings are in accordance to works performed by our group, in which sustained stress resulted in higher levels of reactive oxygen species in the microenvironment [30]. This feature was associated with epigenetic reprogramming of non-tumorigenic murine melanocytes, involving both DNA methylation and histone marks, evaluated at transcriptional and posttranslational molecular levels, respectively [16]. Abaffy et al (2010) also identified pyridine as a unique volatile biomarker of nevus.…”

Section: The Key Role Of Biomarkers In Melanoma Classification Refsupporting

confidence: 88%

Biomarkers as Key Contributors in Treating Malignant Melanoma Metastases

Souza

Morais

Jasiulionis

2012

Dermatology Research and Practice

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Melanoma is a human neurocristopathy associated with developmental defects in the neural crest-derived epidermal melanocytes. At the present time, at least three hypotheses were identified that may explain melanoma aetiology, as follows: (1) a model of linear progression from differentiated melanocytes to metastatic cancer cells (2) a model involving the appearance of melanoma stem-like cells, and (3) an epigenetic progenitor model of cancer. Treating metastatic melanoma is one of the most serious challenges in the 21st century. This is justified because of a subpopulation of cells presenting a remarkable molecular heterogeneity, which is able to explain the drug resistance and the growing mortality rates worldwide. Fortunately, there are now evidences sustaining the importance of genetic, epigenetic, and metabolomic alterations as biomarkers for classification, staging, and better management of melanoma patients. To illustrate some fascinating insights in this field, the genes BRAF V600E and CTLA4 have been recognized as bona fide targets to benefit melanoma patients. Our research attempts to carefully evaluate data from the literature in order to highlight the link between a molecular disease model and the key contribution of biomarkers in treating malignant melanoma metastases.

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“…As the epigenetic modifications can be modulated by changes in the environment, leading to a reprogramming of gene expression patterns in mammals [6], [7], it is plausible to hypothesize that there is a biological relationship between epigenetics and microenvironment-driven changes in gene expression, which would lead to a phenotype-switching in melanomas. In fact, it has become clear that a dynamic reprogramming in epigenetic marks has been positively correlated with aberrant gene expression during melanocytic neoplasia, including our model of study [8]–[11]. Epigenetic information is propagated during somatic cell divisions, and is critical for preserving gene expression patterns and cellular identity.…”

Section: Introductionmentioning

confidence: 98%

Mining Gene Expression Signature for the Detection of Pre-Malignant Melanocytes and Early Melanomas with Risk for Metastasis

et al. 2012

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BackgroundMetastatic melanoma is a highly aggressive skin cancer and currently resistant to systemic therapy. Melanomas may involve genetic, epigenetic and metabolic abnormalities. Evidence is emerging that epigenetic changes might play a significant role in tumor cell plasticity and metastatic phenotype of melanoma cells.Principal findingsIn this study, we developed a systematic approach to identify genes implicated in melanoma progression. To do this, we used the Affymetrix GeneChip Arrays to screen 34,000 mouse transcripts in melan-a melanocytes, 4C pre-malignant melanocytes, 4C11− non-metastatic and 4C11+ metastatic melanoma cell lines. The genome-wide association studies revealed pathways commonly over-represented in the transition from immortalized to pre-malignant stage, and under-represented in the transition from non-metastatic to metastatic stage. Additionally, the treatment of cells with 10 µM 5-aza-2′-deoxycytidine (5AzaCdR) for 48 hours allowed us to identify genes differentially re-expressed at specific stages of melan-a malignant transformation. Treatment of human primary melanocytes with the demethylating agent 5AzaCdR in combination to the histone deacetylase inhibitor Trichostatin A (TSA) revealed changes on melanocyte morphology and gene expression which could be an indicator of epigenetic flexibility in normal melanocytes. Moreover, changes on gene expression recognized by affecting the melanocyte biology (NDRG2 and VDR), phenotype of metastatic melanoma cells (HSPB1 and SERPINE1) and response to cancer therapy (CTCF, NSD1 and SRC) were found when Mel-2 and/or Mel-3-derived patient metastases were exposed to 5AzaCdR plus TSA treatment. Hierarchical clustering and network analyses in a panel of five patient-derived metastatic melanoma cells showed gene interactions that have never been described in melanomas.SignificanceDespite the heterogeneity observed in melanomas, this study demonstrates the utility of our murine melanoma progression model to identify molecular markers commonly perturbed in metastasis. Additionally, the novel gene expression signature identified here may be useful in the future into a model more closely related to translational research.

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Epigenetic reprogramming as a key contributor to melanocyte malignant transformation

Cited by 41 publications

References 57 publications

Epigenetics in Melanoma Development and Drug Resistance

Epigenetics in Melanoma Development and Drug Resistance

Biomarkers as Key Contributors in Treating Malignant Melanoma Metastases

Mining Gene Expression Signature for the Detection of Pre-Malignant Melanocytes and Early Melanomas with Risk for Metastasis

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