Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, 801 S, Paulina Street, Chicago, IL, 60612, USA.
Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Biological Sciences Research Building (BSRB), 6767 Bertner Ave, Houston, TX, USA.
Oncogene. 2020 Feb;39(8):1784-1796. doi: 10.1038/s41388-019-1105-y. Epub 2019 Nov 18.
Cancers in the oral/head & neck region (HNSCC) are aggressive due to high incidence of recurrence and distant metastasis. One prominent feature of aggressive HNSCC is the presence of severely hypoxic regions in tumors and activation of hypoxia-inducible factors (HIFs). In this study, we report that the XPE gene product DDB2 (damaged DNA binding protein 2), a nucleotide excision repair protein, is upregulated by hypoxia. Moreover, DDB2 inhibits HIF1α in HNSCC cells. It inhibits HIF1α in both normoxia and hypoxia by reducing mRNA expression. Knockdown of DDB2 enhances the expression of angiogenic markers and promotes tumor growth in a xenograft model. We show that DDB2 binds to an upstream promoter element in the HIF1Α gene and promotes histone H3K9 trimethylation around the binding site by recruiting Suv39h1. Also, we provide evidence that DDB2 has a significant suppressive effect on expression of the endogenous markers of hypoxia that are also prognostic indicators in HNSCC. Together, these results describe a new mechanism of hypoxia regulation that opposes expression of HIF1Α mRNA and the hypoxia-response genes.
口腔/头颈部癌症（HNSCC）由于复发和远处转移的高发生率而具有侵袭性。侵袭性 HNSCC 的一个显著特征是肿瘤中存在严重缺氧区域和缺氧诱导因子（HIFs）的激活。在这项研究中，我们报告了 XPE 基因产物 DDB2（受损 DNA 结合蛋白 2），一种核苷酸切除修复蛋白，在缺氧时被上调。此外，DDB2 抑制 HNSCC 细胞中的 HIF1α。它通过降低 mRNA 表达在常氧和缺氧条件下均抑制 HIF1α。DDB2 的敲低增强了血管生成标记物的表达，并在异种移植模型中促进肿瘤生长。我们表明 DDB2 结合到 HIF1Α 基因的上游启动子元件，并通过招募 Suv39h1 促进结合位点周围的组蛋白 H3K9 三甲基化。此外，我们提供了证据表明 DDB2 对缺氧内源性标志物的表达具有显著的抑制作用，这些标志物也是 HNSCC 的预后指标。总之，这些结果描述了一种新的缺氧调节机制，该机制对抗 HIF1Α mRNA 和缺氧反应基因的表达。
