Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
Department of Chemistry, Chemistry Research Laboratory, The University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
Sci Rep. 2017 Sep 11;7(1):11094. doi: 10.1038/s41598-017-11658-3.
Regions of hypoxia (low oxygen) occur in most solid tumours and cells in these areas are the most aggressive and therapy resistant. In response to decreased oxygen, extensive changes in gene expression mediated by Hypoxia-Inducible Factors (HIFs) contribute significantly to the aggressive hypoxic tumour phenotype. In addition to HIFs, multiple histone demethylases are altered in their expression and activity, providing a secondary mechanism to extend the hypoxic signalling response. In this study, we demonstrate that the levels of HIF-1α are directly controlled by the repressive chromatin mark, H3K9me3. In conditions where the histone demethylase KDM4A is depleted or inactive, H3K9me3 accumulates at the HIF-1α locus, leading to a decrease in HIF-1α mRNA and a reduction in HIF-1α stabilisation. Loss of KDM4A in hypoxic conditions leads to a decreased HIF-1α mediated transcriptional response and correlates with a reduction in the characteristics associated with tumour aggressiveness, including invasion, migration, and oxygen consumption. The contribution of KDM4A to the regulation of HIF-1α is most robust in conditions of mild hypoxia. This suggests that KDM4A can enhance the function of HIF-1α by increasing the total available protein to counteract any residual activity of prolyl hydroxylases.
缺氧（低氧）区域出现在大多数实体瘤中，这些区域的细胞最具侵袭性和抗治疗性。为了应对氧气减少，缺氧诱导因子（HIFs）介导的广泛基因表达变化对侵袭性缺氧肿瘤表型有重要贡献。除了 HIFs 之外，多种组蛋白去甲基酶的表达和活性也发生改变，为延长缺氧信号反应提供了次要机制。在这项研究中，我们证明 HIF-1α 的水平直接受到抑制性染色质标记 H3K9me3 的控制。在组蛋白去甲基酶 KDM4A 耗尽或失活的情况下，H3K9me3 在 HIF-1α 基因座上积累，导致 HIF-1α mRNA 减少和 HIF-1α 稳定性降低。在缺氧条件下失去 KDM4A 会导致 HIF-1α 介导的转录反应减少，并与肿瘤侵袭性相关特征的减少相关，包括侵袭、迁移和耗氧量。在轻度缺氧条件下，KDM4A 对 HIF-1α 的调节作用最为显著。这表明 KDM4A 可以通过增加总可用蛋白来增强 HIF-1α 的功能，以抵消脯氨酰羟化酶的任何残留活性。
