Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Neoplasia. 2011 Oct;13(10):912-22. doi: 10.1593/neo.11576.
Lung carcinogenesis in humans involves an accumulation of genetic and epigenetic changes that lead to alterations in normal lung epithelium, to in situ carcinoma, and finally to invasive and metastatic cancers. The loss of transforming growth factor β (TGF-β)-induced tumor suppressor function in tumors plays a pivotal role in this process, and our previous studies have shown that resistance to TGF-β in lung cancers occurs mostly through the loss of TGF-β type II receptor expression (TβRII). However, little is known about the mechanism of down-regulation of TβRII and how histone deacetylase (HDAC) inhibitors (HDIs) can restore TGF-β-induced tumor suppressor function. Here we show that HDIs restore TβRII expression and that DNA hypermethylation has no effect on TβRII promoter activity in lung cancer cell lines. TGF-β-induced tumor suppressor function is restored by HDIs in lung cancer cell lines that lack TβRII expression. Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by either activated Ras or epidermal growth factor signaling is involved in the down-regulation of TβRII through histone deacetylation. We have immunoprecipitated the protein complexes by biotinylated oligonucleotides corresponding to the HDI-responsive element in the TβRII promoter (-127/-75) and identified the proteins/factors using proteomics studies. The transcriptional repressor Meis1/2 is involved in repressing the TβRII promoter activity, possibly through its recruitment by Sp1 and NF-YA to the promoter. These results suggest a mechanism for the downregulation of TβRII in lung cancer and that TGF-β tumor suppressor functions may be restored by HDIs in lung cancer patients with the loss of TβRII expression.
人类肺癌的发生涉及遗传和表观遗传变化的积累，这些变化导致正常肺上皮细胞的改变、原位癌，最终导致侵袭性和转移性癌症。肿瘤中转化生长因子β（TGF-β）诱导的肿瘤抑制功能的丧失在这个过程中起着关键作用，我们之前的研究表明，肺癌对 TGF-β的耐药性主要是通过 TGF-β 型 II 受体表达（TβRII）的丧失。然而，关于 TβRII 下调的机制以及组蛋白去乙酰化酶（HDAC）抑制剂（HDIs）如何恢复 TGF-β 诱导的肿瘤抑制功能知之甚少。在这里，我们表明 HDIs 恢复了 TβRII 的表达，并且 DNA 超甲基化对肺癌细胞系中 TβRII 启动子活性没有影响。在缺乏 TβRII 表达的肺癌细胞系中，HDI 恢复了 TGF-β 诱导的肿瘤抑制功能。通过激活 Ras 或表皮生长因子信号转导的丝裂原激活的蛋白激酶/细胞外信号调节激酶途径，通过组蛋白去乙酰化作用下调 TβRII。我们通过与 TβRII 启动子（-127/-75）中的 HDI 反应元件相对应的生物素化寡核苷酸，免疫沉淀了蛋白复合物，并通过蛋白质组学研究鉴定了蛋白/因子。转录抑制因子 Meis1/2 参与抑制 TβRII 启动子活性，可能通过其与 Sp1 和 NF-YA 一起募集到启动子上。这些结果表明了肺癌中 TβRII 下调的机制，并且在 TβRII 表达缺失的肺癌患者中，TGF-β 肿瘤抑制功能可能通过 HDIs 恢复。
