Pharmacology Department, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil.
Department of Urology, University of Southern California, Los Angeles, CA, USA.
Mol Oncol. 2022 May;16(9):1913-1930. doi: 10.1002/1878-0261.13185. Epub 2022 Feb 4.
In addition to mutations, epigenetic alterations are important contributors to malignant transformation and tumor progression. The aim of this work was to identify epigenetic events in which promoter or gene body DNA methylation induces gene expression changes that drive melanocyte malignant transformation and metastasis. We previously developed a linear mouse model of melanoma progression consisting of spontaneously immortalized melanocytes, premalignant melanocytes, a nonmetastatic tumorigenic, and a metastatic cell line. Here, through the integrative analysis of methylome and transcriptome data, we identified the relationship between promoter and/or gene body DNA methylation alterations and gene expression in early, intermediate, and late stages of melanoma progression. We identified adenylate cyclase type 3 (Adcy3) and inositol polyphosphate 4-phosphatase type II (Inpp4b), which affect tumor growth and metastatic potential, respectively. Importantly, the gene expression and DNA methylation profiles found in this murine model of melanoma progression were correlated with available clinical data from large population-based primary melanoma cohorts, revealing potential prognostic markers.
除了突变，表观遗传改变也是恶性转化和肿瘤进展的重要因素。本研究旨在鉴定启动子或基因体 DNA 甲基化诱导基因表达变化的表观遗传事件，从而驱动黑素细胞恶性转化和转移。我们之前开发了一种线性小鼠黑色素瘤进展模型，该模型由自发永生化黑素细胞、癌前黑素细胞、非转移性致瘤细胞系和转移性细胞系组成。在这里，我们通过甲基化组和转录组数据的综合分析，鉴定了黑色素瘤进展早期、中期和晚期中启动子和/或基因体 DNA 甲基化改变与基因表达之间的关系。我们鉴定了分别影响肿瘤生长和转移潜能的腺苷酸环化酶 3（Adcy3）和肌醇多磷酸 4-磷酸酶 II（Inpp4b）。重要的是，在这个黑色素瘤进展的小鼠模型中发现的基因表达和 DNA 甲基化谱与来自大型基于人群的原发性黑色素瘤队列的可用临床数据相关，揭示了潜在的预后标志物。
