<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Molecular and functional characterization of the role of the histone methyltransferase SETDB1 in malignant melanoma"^^ . "Malignant melanoma is the most deadly skin cancer. Clinical studies reported a dramatic\r\nincrease in the incidence of melanoma over the past few years. A very distinctive feature\r\nof melanoma is its high degree of heterogeneity and cellular plasticity. Within the tumor\r\nthere are different genetically defined subpopulations of melanoma cells, which is one of\r\nthe reasons for the low efficacy of targeted therapies. Furthermore, most melanomas\r\nquickly develop a resistance to these therapies, causing tumor relapse. For all these\r\nreasons, gaining an understanding of the molecular and cellular mechanisms driving\r\nmelanoma progression will be important for developing potent therapeutic approaches.\r\nSo far, some key regulatory pathways normally activated in melanoma have been well\r\ndefined, and these pathways are mainly driven by activation of oncogenes like BRAF\r\nand NRAS, with a considerable relevance for clinical practice. However, the\r\nidentification of novel key regulators and pathways is still a challenge and will help to\r\nbetter understand melanoma development and to open up new possibilities to treat\r\ntherapy resistant tumors.\r\nRecent studies and work previously conducted in our laboratory reported that the\r\nhistone methyltransferase SETDB1 plays a major role in melanoma pathogenesis. It has\r\nbeen observed that SETDB1 expression, which correlates with its amplification state in\r\nmelanoma, is also associated with melanoma progression. However, the role of\r\nSETDB1 and its mode of action in melanoma are still unclear.\r\nThe aim of this project is to clarify the role of SETDB1 in melanoma, through the\r\nidentification and functional characterization of SETDB1-mediated molecular\r\nmechanisms. Here, I report that SETDB1 expression caused deep changes in\r\nmelanoma transcriptome resulting in the deregulation of pro- and anti-tumorigenic\r\nfactors. Specifically, SETDB1 induced THBS1 upregulation and suppressed DCT\r\nexpression. SETDB1 functions are dependent on its catalytic SET domain. During\r\nmelanoma progression, SETDB1 promoted important epigenetic alterations such as\r\nchanging the genomic distribution of H3K9me3 and H3K4me1 marks. These histone\r\n2\r\nmodifications impacted the transcription of SETDB1 downstream targets. I could show\r\nthat melanoma cells were sensitive to treatment with the SETDB1-inhibitor mithramycin\r\nA. Mithramycin treatment suppressed SETDB1 expression and tumorigenic properties of\r\nmelanoma cells. Combinatorial treatment with mithramycin and MAPK inhibitors showed\r\nenhanced anti-tumor effects.\r\nTaken together, the findings presented here highlight the crucial functional and\r\nmechanistic role of SETDB1 in melanoma. SETDB1 could be considered as a potential\r\nfuture target for the treatment of melanoma."^^ . "2020" . . . . . . . "Aniello"^^ . "Federico"^^ . "Aniello Federico"^^ . . . . . . "Molecular and functional characterization of the role of the histone methyltransferase SETDB1 in malignant melanoma (PDF)"^^ . . . "PhD thesis_Aniello Federico.PDF"^^ . . "HTML Summary of #26697 \n\nMolecular and functional characterization of the role of the histone methyltransferase SETDB1 in malignant melanoma\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .