HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia
HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia
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DOI：
10.1186/s12881-019-0767-1
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发表时间：
2019-02-26
影响因子：
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通讯作者：
Capasso, Mario
中科院分区：
文献类型：
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作者：
Cimmino, Flora;Avitabile, Marianna;Capasso, Mario
背景：HIF1A(缺氧诱导因子1A)在实体瘤中的表达与肿瘤对治疗方法的抵抗有关。使用直接针对缺氧信号的化合物和HIF1a并不显示出临床有效性，因为实体肿瘤区域的氧浓度变化。HIF1a靶基因在常氧和低氧条件下的表达以及HIF1a/低氧信号的识别可能会改善高危实体瘤患者的预后分层和治疗成功。方法在本研究中，我们结合分析了在常氧和低氧条件下生长的HIF1a表达沉默或未沉默的神经母细胞瘤细胞的RNA表达和DNA甲基化。结果通路分析突出了代谢过程中常氧条件下HIF-1(异二聚体转录因子1)活性和神经元分化过程中缺氧条件下HIF-1活性。缺氧时HIF1a驱动的转录反应依赖于基因调控区DNA甲基化状态的表观遗传控制。此外，低氧水平产生HIF1a依赖或非HIF1a信号，能够根据风险类别对患者进行分层。结论这些发现可能有助于理解低氧水平重塑基因特征的分子机制，并为实体瘤的低氧靶向提供新的方向。
BackgroundHIF1A (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches. The use of compounds direct against hypoxia signaling and HIF1A does not show clinical efficiency because of changeable oxygen concentrations in solid tumor areas. The identification of HIF1A targets expressed in both normoxia and hypoxia and of HIF1A/hypoxia signatures might meliorate the prognostic stratification and therapeutic successes in patients with high-risk solid tumors.MethodsIn this study, we conducted a combined analysis of RNA expression and DNA methylation of neuroblastoma cells silenced or unsilenced for HIF1A expression, grown in normoxia and hypoxia conditions.ResultsThe analysis of pathways highlights HIF-1 (heterodimeric transcription factor 1) activity in normoxia in metabolic process and HIF-1 activity in hypoxia in neuronal differentiation process. HIF1A driven transcriptional response in hypoxia depends on epigenetic control at DNA methylation status of gene regulatory regions. Furthermore, low oxygen levels generate HIF1A-dependent or HIF1A-independent signatures, able to stratify patients according to risk categories.ConclusionsThese findings may help to understand the molecular mechanisms by which low oxygen levels reshape gene signatures and provide new direction for hypoxia targeting in solid tumor.