Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2012 Sep 14;150(6):1135-46. doi: 10.1016/j.cell.2012.07.033.
DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.
DNA 上胞嘧啶的 5 位发生的甲基化（5-mC）是一种关键的表观遗传标记，对于各种生物学和病理学过程都至关重要。5-mC 可以通过 TET 家族的 DNA 羟化酶转化为 5-羟甲基胞嘧啶（5-hmC）。在这里，我们报告说“5-hmC 的缺失”是黑色素瘤的一个表观遗传标志，具有诊断和预后意义。对 5-hmC 的全基因组作图揭示了黑色素瘤表观基因组中 5-hmC 景观的缺失。我们表明，异柠檬酸脱氢酶 2（IDH2）和 TET 家族酶的下调可能是黑色素瘤中 5-hmC 缺失的机制之一。通过重新引入活性 TET2 或 IDH2 在黑色素瘤细胞中重建 5-hmC 景观，可抑制黑色素瘤的生长并增加动物模型中的无肿瘤存活时间。因此，我们的研究揭示了 5-hmC 在黑色素瘤发生发展中的关键功能，并直接将 IDH 和 TET 活性依赖性表观遗传途径与 5-hmC 介导的黑色素瘤进展抑制联系起来，为表观遗传学癌症治疗提供了新策略。
