TRON-Center for Translational Oncology and Immunology GmbH, Mainz, Germany.
Oncogene. 2011 Feb 17;30(7):876-82. doi: 10.1038/onc.2010.481. Epub 2010 Nov 1.
Hypoxia-inducible factor 1α (HIF-1α) is frequently overexpressed in human cancers and controls the expression of several genes that have been implicated in tumor growth and progression. Activity of HIF-1α in cancer cells is regulated at the transcriptional, translational and posttranslational level by multiple inter- and coacting molecular pathways. In this report, we reveal for the first time that tumor-associated CpG demethylation facilitates positive autoregulation of HIF-1α, resulting in amplification of hypoxia-induced transactivation of HIF-1α target genes. The HIF-1α promoter harbors a hypoxia response element that is normally repressed by methylation of a CpG dinucleotide located in the core element. In colon cancer cell lines and in primary colon cancer specimens, however, we found frequent aberrant demethylation of this element, enabling binding of HIF-1α to its own promoter resulting in autotransactivation of HIF-1α expression. Our results provide novel and highly unexpected insights into the complexity of HIF-1α regulation in cancer cells and implicate that tumor-associated CpG demethylation augments HIF-1α-mediated effects on malignant cell growth.
缺氧诱导因子 1α（HIF-1α）在人类癌症中经常过表达，并控制着几个已被涉及肿瘤生长和进展的基因的表达。HIF-1α 在癌细胞中的活性通过多种相互作用和合作的分子途径在转录、翻译和翻译后水平上进行调节。在本报告中，我们首次揭示了肿瘤相关的 CpG 去甲基化有助于 HIF-1α 的正反馈调节，导致缺氧诱导的 HIF-1α 靶基因转录激活的扩增。HIF-1α 启动子含有一个缺氧反应元件，该元件通常被位于核心元件中的一个 CpG 二核苷酸的甲基化所抑制。然而，在结肠癌细胞系和原发性结肠癌标本中，我们发现该元件经常发生异常的去甲基化，从而使 HIF-1α 结合到其自身的启动子上，导致 HIF-1α 表达的自激活。我们的结果为癌症细胞中 HIF-1α 调节的复杂性提供了新颖且出人意料的见解，并表明肿瘤相关的 CpG 去甲基化增强了 HIF-1α 对恶性细胞生长的影响。
