Division of Hematology/Oncology, Robert H Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Oncogene. 2013 Jun 6;32(23):2882-90. doi: 10.1038/onc.2012.297. Epub 2012 Jul 16.
Epigenetic deregulation of gene expression has a role in the initiation and progression of prostate cancer (PCa). The histone methyltransferase MMSET/WHSC1 (Multiple Myeloma SET domain) is overexpressed in a number of metastatic tumors, but its mechanism of action has not been defined. In this work, we found that PCa cell lines expressed significantly higher levels of MMSET compared with immortalized, non-transformed prostate cells. Knockdown experiments showed that, in metastatic PCa cell lines, dimethylation of lysine 36 and trimethylation of lysine 27 on histone H3 (H3K36me2 and H3K27me3, respectively) depended on MMSET expression, whereas depletion of MMSET in benign prostatic cells did not affect chromatin modifications. Knockdown of MMSET in DU145 and PC-3 tumor cells decreased cell proliferation, colony formation in soft agar and strikingly diminished cell migration and invasion. Conversely, overexpression of MMSET in immortalized, non-transformed RWPE-1 cells promoted cell migration and invasion, accompanied by an epithelial-mesenchymal transition (EMT). Among a panel of EMT-promoting genes analyzed, TWIST1 expression was strongly activated in response to MMSET. Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the TWIST1 locus and leads to an increase in H3K36me2, suggesting a direct role of MMSET in the regulation of this gene. Depletion of TWIST1 in MMSET-overexpressing RWPE-1 cells blocked cell invasion and EMT, indicating that TWIST1 was a critical target of MMSET, responsible for the acquisition of an invasive phenotype. Collectively, these data suggest that MMSET has a role in PCa pathogenesis and progression through epigenetic regulation of metastasis-related genes.
表观遗传调控基因表达在前列腺癌（PCa）的发生和发展中起作用。组蛋白甲基转移酶 MMSET/WHSC1（多发性骨髓瘤 SET 域）在许多转移性肿瘤中过表达，但作用机制尚未确定。在这项工作中，我们发现 PCa 细胞系表达的 MMSET 水平明显高于永生化的非转化前列腺细胞。敲低实验表明，在转移性 PCa 细胞系中，组蛋白 H3 赖氨酸 36 二甲基化（H3K36me2）和赖氨酸 27 三甲基化（H3K27me3）取决于 MMSET 的表达，而良性前列腺细胞中 MMSET 的耗竭并不影响染色质修饰。在 DU145 和 PC-3 肿瘤细胞中敲低 MMSET 会降低细胞增殖、软琼脂中的集落形成，并且显著减少细胞迁移和侵袭。相反，在永生化的非转化 RWPE-1 细胞中过表达 MMSET 会促进细胞迁移和侵袭，并伴有上皮间质转化（EMT）。在分析的一组促进 EMT 的基因中，TWIST1 的表达受到 MMSET 的强烈激活。染色质免疫沉淀分析表明 MMSET 与 TWIST1 基因座结合，并导致 H3K36me2 增加，表明 MMSET 直接参与该基因的调节。在过表达 MMSET 的 RWPE-1 细胞中敲低 TWIST1 会阻断细胞侵袭和 EMT，表明 TWIST1 是 MMSET 的关键靶点，负责获得侵袭表型。总的来说，这些数据表明 MMSET 通过对转移相关基因的表观遗传调控在 PCa 的发病机制和进展中起作用。
