Aberrant transforming growth factor β1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer
Aberrant transforming growth factor β1 signaling and SMAD4 nuclear translocation confer epigenetic repression of ADAM19 in ovarian cancer
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DOI：
10.1593/neo.08540
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发表时间：
2008-09-01
期刊：
影响因子：
4.8
通讯作者：
Lin, Huey-Jen L.
中科院分区：
文献类型：
--
作者：
Chan, Michael;Huang, Yi-Wen;Lin, Huey-Jen L.
转化生长因子-β（TGF-β）/SMAD信号传导是一种关键的生长调节途径，在卵巢癌和其他恶性肿瘤中经常失调。尽管已证明TGF-β介导的生长抑制作用的丧失会导致细胞行为异常，但靶基因上TGF-β/SMAD信号传导受损的表观遗传后果尚未得到充分确定。在这项研究中，我们表明，TGF-β 1导致正常卵巢表面上皮细胞的生长抑制，诱导核转位SMAD 4，并上调ADAM 19（解整合素和金属蛋白酶结构域19），一个新发现的TGF-β 1的靶基因。相反，SMAD 4的诱导和核转位在对TGF-β 1刺激难治的卵巢癌细胞中可以忽略不计，并且ADAM 19表达大大降低。此外，在TGF-β 1难治性细胞中，以抑制性组蛋白修饰（三甲基-H3 K27和二甲基-H3 K9）和组蛋白脱乙酰酶为标志的非活性染色质环境与ADAM 19启动子区域相关。然而，在ADAM 19的启动子和第一外显子内发现的CpG岛通常保持未甲基化。尽管生长因子信号传导被破坏与癌症中的表观遗传基因沉默有关，但这是第一个证据表明TGF-β 1信号传导受损可导致抑制性染色质状态的形成和ADAM 19的表观遗传抑制。鉴于亚当斯家族蛋白在正常细胞生长因子调节中的作用，我们认为ADAM 19的表观遗传失调可能有助于卵巢癌的肿瘤过程。
Transforming growth factor-beta (TGF-beta)/SMAD signaling is a key growth regulatory pathway often dysregulated in ovarian cancer and other malignancies. Although loss of TGF-beta-mediated growth inhibition has been shown to contribute to aberrant cell behavior, the epigenetic consequence(s) of impaired TGF-beta/SMAD signaling on target genes is not well established. In this study, we show that TGF-beta 1 causes growth inhibition of normal ovarian surface epithelial cells, induction of nuclear translocation SMAD4, and up-regulation of ADAM19 (a disintegrin and metalloprotease domain 19), a newly identified TGF-beta 1 target gene. Conversely, induction and nuclear translocation of SMAD4 were negligible in ovarian cancer cells refractory to TGF-beta 1 stimulation, and ADAM19 expression was greatly reduced. Furthermore, in the TGF-beta 1 refractory cells, an inactive chromatin environment, marked by repressive histone modifications (trimethyl-H3K27 and dimethyl-H3K9) and histone deacetylase, was associated with the ADAM19 promoter region. However, the CpG island found within the promoter and first exon of ADAM19 remained generally unmethylated. Although disrupted growth factor signaling has been linked to epigenetic gene silencing in cancer, this is the first evidence demonstrating that impaired TGF-beta 1 signaling can result in the formation of a repressive chromatin state and epigenetic suppression of ADAM19. Given the emerging role of ADAMs family proteins in growth factor regulation in normal cells, we suggest that epigenetic dysregulation of ADAM19 may contribute to the neoplastic process in ovarian cancer.