Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
Cancer Res. 2011 Mar 1;71(5):1752-62. doi: 10.1158/0008-5472.CAN-10-3573. Epub 2011 Jan 7.
Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future.
组蛋白 3 赖氨酸 27 三甲基化（H3K27me3）是维持基因沉默的关键表观遗传标记。在肿瘤发生过程中，靶基因中 DNA 甲基化的额外积累被认为协同支持这种表观遗传沉默。然而，两种标记物之间复杂相互作用的分子机制仍有待探索。在这里，我们表明 PI3K/AKT 信号的激活可以作为许多下游靶基因中这种表观遗传加工的触发因素。我们还发现，在癌细胞中可以在相同的基因座上获得 DNA 甲基化，从而在失去 H3K27me3 标记的基因座上加强永久抑制。由于 PI3K/AKT 信号和表观遗传改变之间存在联系，我们进行了表观遗传治疗，同时进行了信号靶向治疗。这些联合治疗在体外和异种移植中协同缓解基因沉默并抑制癌细胞生长。这一新发现对未来改善靶向癌症治疗具有重要意义。
