研究动态
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组蛋白乙酰转移酶1(HAT1)乙酰化缺氧诱导因子2 alpha(HIF2A),以执行缺氧反应。

Histone acetyltransferase 1 (HAT1) acetylates hypoxia-inducible factor 2 alpha (HIF2A) to execute hypoxia response.

发表日期:2023 Mar
作者: Naveen Kumar, Mainak Mondal, Bangalore Prabhashankar Arathi, Nagalingam Ravi Sundaresan, Kumaravel Somasundaram
来源: Bba-Gene Regul Mech

摘要:

低氧水平引起的低氧反应是大多数实体癌症的特征。低氧诱导因子(HIF)在低氧时期调节细胞代谢、存活、增殖和癌症干细胞生长。基因组范围分析识别了一个B型组蛋白乙酰转移酶HAT1,作为胶质母细胞瘤(GBM)中的一个上调和必要的基因。在HAT1沉默的细胞中不同调节基因的GSEA分析表明“低氧”基因集的严重缺失。低氧条件在一个HAT1依赖的方式下诱导了HIF2A而不是HIF1A蛋白质水平的提高。HAT1和HIF2A相互作用并占据VEGFA启动子,作为一个真正的HIF1A/HIF2A靶。HAT1的K512和K596残基的乙酰化在正常oxia和低氧下对HIF2A的稳定是必不可少的,因为HIF2A携带一个或两个K512Q或K596Q的乙酰化效仿突变在HAT1沉默的细胞中表现出稳定的表达。最后,我们证明HAT1-HIF2A轴对低氧促进癌症干细胞维持和重编程至关重要。因此,我们的研究确定了HAT1依赖的HIF2A乙酰化是执行低氧诱导的细胞存活和癌症干细胞生长的关键,因此提出HAT1-HIF2A轴作为潜在的治疗靶标。版权所有©2022 Elsevier B.V.。保留所有权利。
Hypoxic response to low oxygen levels is characteristic of most solid cancers. Hypoxia-inducible factors (HIFs) regulate cellular metabolism, survival, proliferation, and cancer stem cell growth during hypoxia. The genome-wide analysis identified HAT1, a type B histone acetyltransferase, as an upregulated and essential gene in glioblastoma (GBM). GSEA analysis of differentially regulated genes in HAT1 silenced cells identified significant depletion of "hypoxia" gene sets. Hypoxia conditions induced HIF2A, not HIF1A protein levels in glioma cells in a HAT1-dependent manner. HAT1 and HIF2A interacted with each other and occupied the promoter of VEGFA, a bonafide HIF1A/HIF2A target. Acetylation of K512 and K596 residues by HAT1 is essential for HIF2A stabilization under normoxia and hypoxia as HIF2A carrying acetylation mimic mutations at either of these residues (H512Q or K596Q) showed stable expression in HAT1 silenced cells under normoxia and hypoxia conditions. Finally, we demonstrate that the HAT1-HIF2A axis is essential for hypoxia-promoted cancer stem cell maintenance and reprogramming. Thus, our study identifies that the HAT1-dependent acetylation of HIF2A is vital to executing the hypoxia-induced cell survival and cancer stem cell growth, therefore proposing the HAT1-HIF2A axis as a potential therapeutic target.Copyright © 2022 Elsevier B.V. All rights reserved.