Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium.
Mouse Histopathology Core Facility, VIB Center for Brain & Disease Research, Leuven, Belgium.
Cancer Res. 2019 Feb 1;79(3):482-494. doi: 10.1158/0008-5472.CAN-18-1214. Epub 2018 Dec 11.
Although numerous epigenetic aberrancies accumulate in melanoma, their contribution to initiation and progression remain unclear. The epigenetic mark 5-hydroxymethylcytosine (5hmC), generated through TET-mediated DNA modification, is now referred to as the sixth base of DNA and has recently been reported as a potential biomarker for multiple types of cancer. Loss of 5hmC is an epigenetic hallmark of melanoma, but whether a decrease in 5hmc levels contributes directly to pathogenesis or whether it merely results from disease progression-associated epigenetic remodeling remains to be established. Here, we show that NRAS-driven melanomagenesis in mice is accompanied by an overall decrease in 5hmC and specific 5hmC gains in selected gene bodies. Strikingly, genetic ablation of in mice cooperated with oncogenic NRAS to promote melanoma initiation while suppressing specific gains in 5hmC. We conclude that TET2 acts as a barrier to melanoma initiation and progression, partly by promoting 5hmC gains in specific gene bodies. SIGNIFICANCE: This work emphasizes the importance of epigenome plasticity in cancer development and highlights the involvement of druggable epigenetic factors in cancer.
虽然黑色素瘤中存在许多表观遗传异常，但它们对肿瘤发生和进展的贡献仍不清楚。表观遗传标记 5-羟甲基胞嘧啶（5hmC）是通过 TET 介导的 DNA 修饰产生的，现在被称为 DNA 的第六个碱基，并被最近报道为多种癌症的潜在生物标志物。5hmC 的缺失是黑色素瘤的一个表观遗传标志，但 5hmc 水平的降低是否直接导致发病机制，或者是否仅仅是疾病进展相关的表观遗传重塑的结果，仍有待确定。在这里，我们表明，NRAS 驱动的小鼠黑色素瘤发生伴随着 5hmC 的总体降低和特定基因体内 5hmC 的特定增加。引人注目的是，在小鼠中遗传敲除 与致癌性 NRAS 合作促进黑色素瘤的起始，同时抑制特定的 5hmC 获得。我们得出结论，TET2 作为黑色素瘤起始和进展的障碍，部分是通过促进特定基因体内 5hmC 的获得。意义：这项工作强调了表观基因组可塑性在癌症发展中的重要性，并强调了可用药理表观遗传因素在癌症中的参与。
